Autoimmune diseases (AID) are inherited as complex genetic diseases. Different Autoimmune diseases have been found to cluster in families and are believed to share some common etiological factors. With the exception of major histocompatibility complex (MHC) genes contributing susceptibility to these diseases have been difficult to identify. CD152 has emerged as one such candidate unifying several autoimmune diseases. We here review the evidence that CD152 constitutes a general susceptibility factor for multiple autoimmune diseases and discuss how CD152 and other co-stimulatory pathways may contribute to autoimmune pathogenesis.