Phosphatidylinositol (PI) is distinct from other phospholipids, possessing a head group that can be modified by phosphorylation at multiple positions to generate unique signaling molecules collectively known as phosphoinositides. The set of kinases and phosphatases that regulate PI metabolism are conserved throughout eukaryotic evolution, and numerous studies have demonstrated that phosphoinositides regulate a diverse spectrum of cellular processes, including vesicle transport, cell proliferation, and cytoskeleton organization. Over the past two decades, nearly all PI derivatives have been shown to interact directly with cellular proteins to affect their localization and/or activity. Additionally, there is growing evidence, which suggests that phosphoinositides may also affect local membrane topology. Here, we focus on the role of phosphoinositides in membrane trafficking and underscore the significant role that yeast has played in the field.