Here we review the environmental and genetic manipulations that link cellular and organismal metabolism to aging. In particular, we explore how nutrients are sensed and how various intracellular energy nodes seem to coordinate distinct metabolic alterations linked to extended longevity. In addition, the role of mitochondria as both a metabolic and signaling organelle is discussed. Finally, we review a host of new targeted pharmacological approaches that attempt to exploit the connection between aging and metabolism to treat a wide range of age-related diseases. Together, these insights are beginning to reveal answers to century-old mysteries and are providing a future road map for the rational extension of lifespan.