Pasupathy and Homer-Vanniasinkam provide a brief overview of IP, systematically surveying the surgical implications of this phenomenon in a variety of organs. A recurrent theme is the disconnect between the extensive experimental evidence indicating the potential to exploit this phenomenon to improve outcome after ischemic stress and the dearth of actual human data demonstrating clinical benefit. This disconnect is obviously not limited to the field of IP. One of the major motivating factors behind the new “roadmap,” outlined by Elias Zerhouni, MD, director of the National Institutes of Health, is the need to overcome the so-called translational block that prevents basic research advances from moving into everyday clinical practice. Despite nearly 2 decades of research into IP, the upstream events that trigger the adaptive response to sublethal ischemia, and the downstream targets that mediate protection, remain only partially understood. This review does not delve deeply into nuances such as the distinction between early and late preconditioning, the ability of pharmacologic agents to mimic IP, distinctions among prevention of initial cell injury, attenuation of postischemic apoptosis, and enhancement of reparative responses. Among the major difficulties in applying IP in the clinical setting include the narrow window of opportunity during which preconditioning can be elicited, variations in conditions from organ to organ and from patient to patient, and the confounding influence of comorbidities such as diabetes or other diseases. For this reason, pharmacologic rather than true ischemic preconditioning may hold more promise. A number of signaling pathways have emerged as particularly attractive for intervention, including hypoxia-inducible factor and hypoxia-regulated genes, protein kinase C, and multiple stress-activated kinase cassettes. Clearly, there is a continuing need for academic surgeons in diverse subspecialties to participate in the translational research needed to nudge IP beyond laboratory phenomenology into practical clinical relevance.