Phosphatidylinositol lipids are signaling molecules involved in nearly all aspects of cellular regulation. Production of phosphatidylinositol 4-phosphate (PI4P) has long been recognized as one of the first steps in generating poly-phosphatidylinositol phosphates involved in actin organization, cell migration, and signal transduction. In addition, progress over the last decade has brought to light independent roles for PI4P in membrane trafficking and lipid homeostasis. Here, we describe recent advances that reveal the breadth of processes regulated by PI4P, the spectrum of PI4P effectors, and the mechanisms of spatiotemporal control that coordinate crosstalk between PI4P and cellular signaling pathways.