The phosphoinositide-3-kinase (PI3K) family of lipid kinases has been well conserved from yeast to mammals. In this evolutionary perspective on the PI3K family, we discuss the prototypical properties of PI3Ks: 1) the utilization of sparse but specifically localized lipid substrates; 2) the nucleation signaling complexes at membrane-targeted sites; and 3) the integration of intracellular signaling with extracellular cues. Together, these three core properties serve to establish order within the entropic environment of the cell. Many human diseases, including cancer and diabetes, are the direct result of loss or defects in one or more of these core properties, putting much hope in the clinical use of PI3K inhibitors singly and in combination to restore order within diseased tissues.