What is the structure of water?
Researchers continue to tussle over how many bonds each H2O molecule makes with its nearest neighbors.

What is the nature of the glassy state?
Molecules in a glass are arranged much like those in liquids but are more tightly packed. Where and why does liquid end and glass begin?

Are there limits to rational chemical synthesis?
The larger synthetic molecules get, the harder it is to control their shapes and make enough copies of them to be useful. Chemists will need new tools to keep their creations growing.

What is the ultimate efficiency of photovoltaic cells?
Conventional solar cells top out at converting 32% of the energy in sunlight to electricity. Can researchers break through the barrier?

Will fusion always be the energy source of the future?
It's been 35 years away for about 50 years, and unless the international community gets its act together, it'll be 35 years away for many decades to come.

What drives the solar magnetic cycle?
Scientists believe differing rates of rotation from place to place on the sun underlie its 22-year sunspot cycle. They just can't make it work in their simulations. Either a detail is askew, or it's back to the drawing board.

How do planets form?
How bits of dust and ice and gobs of gas came together to form the planets without the sun devouring them all is still unclear. Planetary systems around other stars should provide clues.

What causes ice ages?
Something about the way the planet tilts, wobbles, and careens around the sun presumably brings on ice ages every 100,000 years or so, but reams of climate records haven't explained exactly how.

What causes reversals in Earth's magnetic field?
Computer models and laboratory experiments are generating new data on how Earth's magnetic poles might flip-flop. The trick will be matching simulations to enough aspects of the magnetic field beyond the inaccessible core to build a convincing case.

Are there earthquake precursors that can lead to useful predictions?
Prospects for finding signs of an imminent quake have been waning since the 1970s. Understanding faults will progress, but routine prediction would require an as-yet-unimagined breakthrough.

Is there--or was there--life elsewhere in the solar system?
The search for life--past or present--on other planetary bodies now drives NASA's planetary exploration program, which focuses on Mars, where water abounded when life might have first arisen.

What is the origin of homochirality in nature?
Most biomolecules can be synthesized in mirror-image shapes. Yet in organisms, amino acids are always left-handed, and sugars are always right-handed. The origins of this preference remain a mystery.

Can we predict how proteins will fold?
Out of a near infinitude of possible ways to fold, a protein picks one in just tens of microseconds. The same task takes 30 years of computer time.

How many proteins are there in humans?
It has been hard enough counting genes. Proteins can be spliced in different ways and decorated with numerous functional groups, all of which makes counting their numbers impossible for now.

How do proteins find their partners?
Protein-protein interactions are at the heart of life. To understand how partners come together in precise orientations in seconds, researchers need to know more about the cell's biochemistry and structural organization.

How many forms of cell death are there?
In the 1970s, apoptosis was finally recognized as distinct from necrosis. Some biologists now argue that the cell death story is even more complicated. Identifying new ways cells die could lead to better treatments for cancer and degenerative diseases.

What keeps intracellular traffic running smoothly?
Membranes inside cells transport key nutrients around, and through, various cell compartments without sticking to each other or losing their way. Insights into how membranes stay on track could help conquer diseases, such as cystic fibrosis.

What enables cellular components to copy themselves independent of DNA?
Centrosomes, which help pull apart paired chromosomes, and other organelles replicate on their own time, without DNA's guidance. This independence still defies explanation.

What roles do different forms of RNA play in genome function?
RNA is turning out to play a dizzying assortment of roles, from potentially passing genetic information to offspring to muting gene expression. Scientists are scrambling to decipher this versatile molecule.

What role do telomeres and centromeres play in genome function?
These chromosome features will remain mysteries until new technologies can sequence them.

Why are some genomes really big and others quite compact?
The puffer fish genome is 400 million bases; one lungfish's is 133 billion bases long. Repetitive and duplicated DNA don't explain why this and other size differences exist.

What is all that "junk" doing in our genomes?
DNA between genes is proving important for genome function and the evolution of new species. Comparative sequencing, microarray studies, and lab work are helping genomicists find a multitude of genetic gems amid the junk.

How much will new technologies lower the cost of sequencing?
New tools and conceptual breakthroughs are driving the cost of DNA sequencing down by orders of magnitude. The reductions are enabling research from personalized medicine to evolutionary biology to thrive.

How do organs and whole organisms know when to stop growing?
A person's right and left legs almost always end up the same length, and the hearts of mice and elephants each fit the proper rib cage. How genes set limits on cell size and number continues to mystify.

How can genome changes other than mutations be inherited?
Researchers are finding ever more examples of this process, called epigenetics, but they can't explain what causes and preserves the changes.

How is asymmetry determined in the embryo?
Whirling cilia help an embryo tell its left from its right, but scientists are still looking for the first factors that give a relatively uniform ball of cells a head, tail, front, and back.

How do limbs, fins, and faces develop and evolve?
The genes that determine the length of a nose or the breadth of a wing are subject to natural and sexual selection. Understanding how selection works could lead to new ideas about the mechanics of evolution with respect to development.

What triggers puberty?
Nutrition--including that received in utero--seems to help set this mysterious biological clock, but no one knows exactly what forces childhood to end.

Are stem cells at the heart of all cancers?
The most aggressive cancer cells look a lot like stem cells. If cancers are caused by stem cells gone awry, studies of a cell's "stemness" may lead to tools that could catch tumors sooner and destroy them more effectively.

Is cancer susceptible to immune control?
Although our immune responses can suppress tumor growth, tumor cells can combat those responses with counter-measures. This defense can stymie researchers hoping to develop immune therapies against cancer.

Can cancers be controlled rather than cured?
Drugs that cut off a tumor's fuel supplies--say, by stopping blood-vessel growth--can safely check or even reverse tumor growth. But how long the drugs remain effective is still unknown.

Is inflammation a major factor in all chronic diseases?
It's a driver of arthritis, but cancer and heart disease? More and more, the answer seems to be yes, and the question remains why and how.

How do prion diseases work?
Even if one accepts that prions are just misfolded proteins, many mysteries remain. How can they go from the gut to the brain, and how do they kill cells once there, for example.

How much do vertebrates depend on the innate immune system to fight infection?
This system predates the vertebrate adaptive immune response. Its relative importance is unclear, but immunologists are working to find out.

Does immunologic memory require chronic exposure to antigens?
Yes, say a few prominent thinkers, but experiments with mice now challenge the theory. Putting the debate to rest would require proving that something is not there, so the question likely will not go away.

Why doesn't a pregnant woman reject her fetus?
Recent evidence suggests that the mother's immune system doesn't "realize" that the fetus is foreign even though it gets half its genes from the father. Yet just as Nobelist Peter Medawar said when he first raised this question in 1952, "the verdict has yet to be returned."

What synchronizes an organism's circadian clocks?
Circadian clock genes have popped up in all types of creatures and in many parts of the body. Now the challenge is figuring out how all the gears fit together and what keeps the clocks set to the same time.

How do migrating organisms find their way?
Birds, butterflies, and whales make annual journeys of thousands of kilometers. They rely on cues such as stars and magnetic fields, but the details remain unclear.

Why do we sleep?
A sound slumber may refresh muscles and organs or keep animals safe from dangers lurking in the dark. But the real secret of sleep probably resides in the brain, which is anything but still while we're snoring away.

Why do we dream?
Freud thought dreaming provides an outlet for our unconscious desires. Now, neuroscientists suspect that brain activity during REM sleep--when dreams occur--is crucial for learning. Is the experience of dreaming just a side effect?

Why are there critical periods for language learning?
Monitoring brain activity in young children--including infants--may shed light on why children pick up languages with ease while adults often struggle to learn train station basics in a foreign tongue.