The insulin/IGF-1 signaling pathway is evolutionarily conserved and its function is mediated largely by FOXO transcription factors. Reduced insulin/IGF-1 signaling leads to translocation of FOXO proteins from the cytoplasm to the nucleus where they activate a set of genes that mediate oxidative stress, heat shock, and xenobiotic responses, innate immunity, metabolism, and autophagy. Disruptions in the insulin/IGF-1 signaling pathway affect life span in many species. Over the past two decades, the function of these FOXO proteins in age-related diseases has been extensively studied, in the model organism Caenorhabditis elegans as well as in humans. In this review we investigate the mechanisms by which FOXO proteins influence the development of age-related disease pathways in both species.