CD40, also known as TNFRSF5, is a transmembrane TNF superfamily receptor that is expressed on the surface of B cells, dendritic cells, macrophages, monocytes and platelets, as well as endothelial and epithelial cells. Interaction of CD40 with CD40 Ligand leads to the aggregation of CD40 molecules resulting in the initiation of bidirectional intracellular signaling in both CD40 and CD40 Ligand expressing cells. This interaction promotes B cell activation and T cell-dependent humoral responses. CD40 serves multiple functions in both hematopoietic and epithelial cancers and is a target for tumor immunotherapy. Dysregulation of CD40/CD40 Ligand expression and interactions contributes to disease severity in AIDS, atherosclerosis, atherothrombosis, and restenosis.