We use the nematode C. elegans as a model system for studying the function and regulation of FoxO transcription factors (TFs) in development and aging. The role of FoxO TFs in promoting longevity is evolutionarily conserved. In mammals, FoxO TFs are targets of insulin and insulin-like growth factor-1 (IGF-1) signaling that control metabolic homeostasis and influence tumorigenesis. Thus, understanding FoxO function and regulation may lead to the development of new strategies to treat common human diseases such as Type 2 diabetes and cancer. We have discovered several novel conserved FoxO regulators in C. elegans, and we have also identified key conserved FoxO target genes that are required for FoxO-dependent life span extension. Our current efforts are focused on how these genes influence FoxO activity and action in both C. elegans and mouse models of human disease.