Thanks to the revolutions in information technology, human "-omics" research, and intricate medical device development, academic health centers (AHCs) now have an unparalleled potential to become translational engines that both generate basic science advances and then translate them into human studies and, ultimately, into improved health care. However, AHC infrastructures have traditionally been optimized to foster basic research. Now modifications must be made to meet these expanded roles of AHCs, from providing fundamental biomedical insights to first-in-human interventions and, if warranted, to larger randomized clinical trials. Eventually, AHCs must integrate these improved treatments into patient care. Challenges to this process have been defined by the Institute of Medicine. Building the appropriate infrastructures for human investigation and stabilizing the careers of young physicians essential to these translational events have become critical needs that will require systemic investments if AHCs are to respond to these biological revolutions and fulfill their promise.