IGF-I is important for fetal and post-natal development, but it also controls tissue homeostasis throughout life via regulation of cell proliferation and apoptosis. This review summarizes our current understanding of how IGF-I receptor signaling interferes with the apoptotic machinery of the cell. IGF-I acts at different control points of apoptosis, including the Bcl-2 family proteins, inhibitors of caspases and signaling of death-inducing receptors. The main focal point of IGF-I is the regulation of Bcl-2 family proteins. Several signaling pathways converge to both the phosphorylation and transcriptional regulation of these proteins. This phenomenon may explain the efficacy of IGF-I as an inhibitor of apoptosis in many different cell types and in the presence of different apoptogenic stimuli.