Due to the wide spectrum of clinical manifestations and their epidemiological dimensions, autoimmune diseases represent an important medical issue. They are the consequence of the loss of immune tolerance to autoantigens, which in turn is a result of the interaction of environmental, as well as genetic factors. The predisposing role of HLA antigens is widely accepted; nonetheless, it does not fully explain the occurrence of autoimmune disorders. In this topical review, we present the current knowledge on the role of some non-HLA genes (ICOS, CD28 and CTLA-4 in particular) in the development of autoimmunity. (Fig. 1, Ref: 106.)