CD40 is a TNF receptor superfamily member expressed on both immune and non-immune cells. Interactions between B cell-expressed CD40 and its binding partner, CD40L, predominantly expressed on activated CD4+ T cells, play a critical role in promoting germinal center formation and the production of class-switched antibodies. Non-hematopoietic cells expressing CD40 can also engage CD40L and trigger a pro-inflammatory response. The CD40-CD40L axis has been implicated in a variety of clinical settings including cardiovascular disease and transplantation. Also, various results support a role for the CD40 pathway in autoimmune disease and suggest that aberrant CD40 signaling could contribute to the initiation or maintenance of pathogenic autoimmune responses.