Aging is a complex, multifactorial process that is likely influenced by the activities of a range of biological pathways. Genetic approaches to identify genes modulating longevity have been highly successful and recent efforts have extended these studies to mammalian aging. A variety of genetic models have been reported to have enhanced lifespan and, similarly, many genetic interventions lead to progeroid phenotypes. Here, we detail and evaluate both sets of models, focusing on the insights they provide about the molecular processes modulating aging and the extent to which mutations conferring progeroid pathologies really phenocopy accelerated aging.