Adaptor proteins (APs) are critical components of the cellular membrane transport machinery. They mediate cargo selection during endocytosis and intracellular vesicular trafficking. Five AP complexes have been characterized (AP1-5), and together their roles extend to diverse cellular processes including homeostasis of membranous organelles, membrane protein turnover, and immune responses. The evolution of Human Immunodeficiency Virus type 1 (HIV-1) has exploited these complexes, enabling immune evasion and the assembly of maximally infectious particles. HIV-1 Nef interacts with AP1 and AP2 to manipulate intracellular trafficking and downregulate immune-related proteins such as CD4 and MHC-I. Vpu also co-opts AP1 and AP2, modulating the innate defense protein BST2 (tetherin) and facilitating the release of virions from infected cells. The envelope glycoprotein (Env) hijacks AP complexes to reduce its expression at the cell surface and potentially to support incorporation into virus particles. Some data suggest that Gag co-opts AP3 to drive assembly at intracellular compartments. In principle, targeting the molecular interfaces between HIV-1 proteins and AP complexes is a promising therapeutic approach. Blocking these interactions should impair HIV-1’s ability to produce infectious particles and evade immune defenses, leading to novel antivirals and facilitating cure.