A fundamental imperative for mammalian cells is to coordinate cell metabolism and growth with environmentally induced stress. This review focuses on three highly integrated networks—the phosphoinositide 3-kinase (PI3K) signaling cascade, intermediate metabolism, and autophagy—that work together to maintain cellular homeostasis under basal conditions and to drive cell-mass accumulation and cell cycle progression in the presence of appropriate mitogenic stimuli. Dysfunction within any one of these networks results in compensatory responses from the other networks. These responses underpin several pathologies associated with major human diseases such as cancer. We discuss the PI3K, metabolism, and autophagy networks and provide selected insights into internetwork cross-talk mechanisms. In recognition of the extensive interactions observed in both healthy and diseased cells, we propose that the three networks be merged into a “metabolism-signaling supernetwork.” A detailed understanding of this supernetwork will facilitate the development of novel therapies for cancer and other complex diseases.