New mechanistic findings on a key HIV enzyme could help advance AIDS drug design, according to a report in Science (2008, 322, 1092). Reverse transcriptase (RT) is an essential enzyme in the life cycle of HIV and a target of AIDS drugs such as azidothymidine (AZT). But aspects of RT's mechanism have remained a mystery. Although the mechanism has been studied by crystallography and other techniques, the acrobatic moves RT undergoes while converting HIV's RNA genome into DNA for incorporation into host cells have been hard to follow. Harvard University's Xiaowei Zhuang and coworkers have now carried out a painstaking study using fluorescence resonance energy transfer—a technique with a powerful ability to probe intermolecular interactions—was used to analyze RT's catalytic pathway. The study shows how RT slides along its nucleic acid substrates and flips into binding orientations that support different catalytic functions. An independent commentary in the same issue of Science notes that the work "vividly illustrates that RT has a remarkable dynamic flexibility that contributes to more efficient replication."