Following 3 decades of extensive research into PI3K signaling, it is now evidently clear that the underlying network does not equate to a simple ON/OFF switch. This is best illustrated by the multifaceted nature of the many diseases associated with aberrant PI3K signaling, including common cancers, metabolic disease, and rare developmental disorders. However, we are still far from a complete understanding of the fundamental control principles that govern the numerous phenotypic outputs that are elicited by activation of this well-characterized biochemical signaling network, downstream of an equally diverse set of extrinsic inputs. At its core, this is a question on the role of PI3K signaling in cellular information processing and decision making. Here, we review the determinants of accurate encoding and decoding of growth factor signals and discuss outstanding questions in the PI3K signal relay network. We emphasize the importance of quantitative biochemistry, in close integration with advances in single-cell time-resolved signaling measurements and mathematical modeling.