Increased longevity has been achieved by genetic and environmental manipulations in model organisms, from nematodes to mammals. Genes that can extend life span when altered are referred to as “gerontogenes.” The last several years have seen a dramatic increase in the number of identified gerontogenes (approximately seventy-four). The vast majority of these genes have been identified in the nematode, Caenorhabditis elegans. These genes include age-1 (a phosphatidylinositol 3-OH kinase gene) and daf-2 (an insulin-like receptor gene), as well as genes mediating behavior, metabolism, reproduction and sensory perception. age-1 and daf-2 play a role in a hormonal signaling cascade similar to the mammalian insulin / IGF-1 pathways. The age-1 / daf-2 signal functions to shorten life span and repress the positive regulators of life span, daf-16 and old-1. Similarly, studies of Dwarf mice indicate that the growth hormone-IGF-1 axis may play a role in regulating longevity. Signals from certain tissues, such as sensory neurons and gonads, also regulate life span in C. elegans. The gonadal signal is dependent on the daf-9 cytochrome P450 gene and the daf-12 steroid receptor gene, implicating roles of steroid hormones in longevity. Moreover, increased resistance to intrinsic and environmental stresses [heat, UV, and reactive oxygen species (ROS)] has been shown to be intimately related to increased longevity in a variety of species. ROS scavengers, including superoxide dismutase (SOD) and SOD mimetics, can extend life span in the fruit fly Drosophila melanogaster and in C. elegans, respectively. We suggest that environmental and intrinsic stresses, depending on the evolutionary niche occupied by the species, are key factors that control life span and aging. In summary, cellular signals regulate systemic mechanisms that play a role in stress resistance and also affect longevity.