This week saw the publication of the second of two papers identifying mutations that give H5N1 the ability to spread through the air between ferrets. The papers, the latest1 from a group led by Ron Fouchier at the Erasmus Medical Center in Rotterdam, the Netherlands, and the earlier one2 by Yoshihiro Kawaoka at the University of Wisconsin-Madison and his colleagues, have been controversial because they offer what some see as a recipe for disaster — that they increase the risk of accidental or intentional release of a deadly human pathogen. But what is most unsettling about them, say many in the flu community, is the evidence they provide that the wild virus could spark a pandemic on its own. That threat makes the outstanding scientific mysteries about this tiny RNA virus — its genome just 14,000 letters long — even more pressing. Here are five of the biggest puzzles, and what researchers are doing to solve them.