Calorie restriction and reduced somatotropic (growth hormone and insulin-like growth factor-1) signaling have a widespread though not universal ability to extend life. These interventions are considered central tools to understanding the downstream events that lead to the increase in healthy life span. As these approaches have been validated, the animals phenotyped, and the mechanisms proposed, many challenges have emerged. In this article, we give several examples and propose several considerations, opportunities, and approaches that may identify major mechanisms through which these interventions exert their effects, and which may lead to drug therapy to increase "health span."