Many of the genes that affect aging and longevity in model organisms, such as mice, fruit flies, and worms, have human homologs. This article reviews several genetic pathways that may extend lifespan through effects on aging, rather than through effects on diseases such as atherosclerosis or cancer. These include some of the genes involved in the regulation of DNA repair and nuclear structure, which cause the progeroid syndromes when mutated, as well as those that may affect telomere length, since shorter telomeres have been associated with shorter survival. Other potential longevity genes, such as sirtuins, are involved in regulating the response to cellular stress, including caloric restriction. The best-studied pathway involves insulin and insulin-like growth factor 1 signaling; mutations in homologs of these genes have extended lifespan up to sixfold in model organisms. Other potential candidates include mitochondrial DNA and the genes that regulate the inflammatory response. Despite the challenges in study design and analysis that face investigators in this area, the identification of genetic pathways that regulate longevity may suggest potential targets for therapy.