Small molecules with the ability to extend mammalian lifespan have recently been discovered. SIRT1-activating compounds (STACs) represent a unique class of drugs that target a conserved longevity pathway. Remarkably, in addition to extending mouse lifespan, STACs demonstrate the ability to treat and prevent a number of age-related pathologies, including type II diabetes, cancer, neurodegeneration, cardiovascular disease, inflammation, and infertility. This chapter discusses the biology underlying the sirtuin longevity pathway and the development and biochemistry of STACs. In addition, it summarizes the effects of STACs on aging and age-related disease in experimental systems, and highlights the challenges faced when translating these findings to the clinic.