T cell costimulatory and coinhibitory pathways are essential orchestrators and regulators of the adaptive immune response. In recent years, the costimulatory CD28 receptor and B7 ligand families have been expanded to include a total of four and seven members, respectively. Several polymorphisms, mutations, and deletions in both regulatory and protein-coding regions of these genes have subsequently been discovered and evaluated for genetic linkage to various human diseases. Here, we review this evidence as we discuss T cell costimulation and coinhibition in the context of genetic susceptibility to autoimmunity, cancer, and other diseases. As we gain further insight into the functional significance and mechanism of these immunoregulatory pathways by both genetic and immunological approaches, these receptors and ligands are poised to become key targets for immunotherapy.