The discovery of new functions for CD154 and CD40 molecules has expanded our knowledge to claim that CD154 plays well beyond its postulated role in adaptive immunity. Active research in this area has outlined an important role of CD154 and its receptor CD40 in the physiopathology of autoimmunity. CD154/CD40 interactions have been shown to underlay inflammatory events characterizing autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosous, and multiple sclerosis. Besides CD40, three additional receptors were recently discovered for CD154, namely, αIIbβ3, α5β1 and Mac-1 integrins. This review gives an overview on CD154 and its receptors, and outlines the function of CD154/CD40 interactions in both normal and autoimmune states. Moreover, the potential usefulness of various CD154-interfering agents in treatment/prevention of autoimmune events is discussed.