In multicellular organisms, concerted actions of different tissues are regulated inside single cells by signal transduction mechanisms that, subsequently to hormones sensing, trigger intracellular responses. In recent years, increasing evidence indicates phosphoinositide 3-kinases (PI3K) as crucial signal transducing elements that regulate communication across the plasma membrane. PI3K generate lipid secondary messengers that trigger a plethora of intracellular responses ranging from metabolic regulation to cell proliferation, survival, and migration. The growing number of hormones that relay signals by activating PI3K suggests not only multiple roles of these enzymes in the regulation of different physiological responses but also a way by which common reactions can be stimulated by different inputs. This review will thus focus on the different pathways that converge on PI3K activation, with particular attention to the paradigmatic PI3K involvement in insulin signaling.