The cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) and programmed death 1 (PD-1) / programmed death-ligand 1 (PD-L1) immune checkpoints are negative regulators of the T-cell immune function. Inhibition of these targets, resulting in an increased activation of the immune system, has led to new immunotherapies for melanoma, non–small cell lung cancer, and other cancers. To set the stage for the impressive clinical data that have been produced with these agents, this introductory article will describe the similarities and differences of both pathways and will touch upon the implications of their inhibition.