AP2 is the best-characterized member of the family of heterotetrameric clathrin adaptor complexes that play pivotal roles in many vesicle trafficking pathways within the cell. AP2 functions in clathrin-mediated endocytosis, the process whereby cargo enters the endosomal system from the plasma membrane. We describe the structure of the 200 kDa AP2 "core" (α trunk, β2 trunk, μ2, and σ2) complexed with the polyphosphatidylinositol headgroup mimic inositolhexakisphosphate at 2.6 Å resolution. Two potential polyphosphatidylinositide binding sites are observed, one on α and one on μ2. The binding site for Yxxφ endocytic motifs is buried, indicating that a conformational change, probably triggered by phosphorylation in the disordered μ2 linker, is necessary to allow Yxxφ motif binding. A model for AP2 recruitment and activation is proposed.