Insulin and leptin are critical metabolic hormones that play essential but distinct roles in regulating the physiologic switch between the fed and starved states. The discoveries of insulin and leptin, in 1922 and 1994, respectively, arose out of radically different scientific environments. Despite the dearth of scientific tools available in 1922, insulin’s discovery rapidly launched a life-saving therapy for what we now know to be type I diabetes, and continually enhanced insulin therapeutics are now effectively applied to both major forms of this increasingly prevalent disease. In contrast, although the discovery of leptin provided deep insights into the regulation of central nervous system energy balance circuits, as well as an effective therapy for an extremely rare form of obesity, its therapeutic impact beyond that has been surprisingly limited. Despite an enormous accumulated body of information, many important questions remain unanswered about the mechanisms of action and role in disease of both hormones. Additionally, although many decades apart, both discoveries reveal the complexities inherent to scientific collaboration and the assignment of credit, even when the efforts are spectacularly successful.