Since 1997, when human infections with a highly pathogenic (HP) avian influenza A virus (AIV) subtype H5N1 - previously infecting only birds - were identified in a Hong Kong outbreak, global attention has focused on the potential for this virus to cause the next pandemic. From December 2003, an unprecedented H5N1 epizootic in poultry and migrating wild birds has spread across Asia and into Europe, the Middle East, and Africa. Humans in close contact with sick poultry and on rare occasion with other infected humans, have become infected. As of early March 2007, 12 countries have reported 167 deaths among 277 laboratory-confirmed human infections to WHO. WHO has declared the world to be in Phase 3 of a Pandemic Alert Period. This paper reviews the evolution of HP AIV H5N1, molecular changes that enable AIVs to infect and replicate in human cells and spread efficiently from person-to-person, and strategies to prevent the emergence of a pandemic virus.