Summary: The binding of Programmed Cell Death Protein 1 (PD-1), a receptor expressed on activated T cells, to its ligands, PD-L1 and PD-L2, negatively regulates immune responses. The PD-1 ligands are found on most cancers, and PD-1:PD-L1/2 interaction inhibits T cell activity and allows cancer cells to escape immune surveillance. The PD-1:PD-L1/2 pathway is also involved in regulating autoimmune responses, making these proteins promising therapeutic targets for a number of cancers, as well as multiple sclerosis, arthritis, lupus, and type I diabetes.