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BAFF and APRIL are two members of the TNF superfamily that are secreted by activated myeloid cells and have costimulatory activity on B cells. BAFF/APRIL signaling regulates a diverse range of biological processes, including cell differentiation, proliferation, survival, and effector functions. Dysregulation of the BAFF/APRIL system has been linked to several inflammatory conditions, specifically autoimmune diseases. Elevated levels of BAFF and APRIL have been reported in autoimmune SLE patients. Both BAFF and APRIL have been described as homotrimeric molecules, a feature common to members of the TNF superfamily. But APRIL and BAFF can form active heterotrimer molecules when co-expressed, and circulating heterotrimer exists in serum samples of patients with systemic immune rheumatic diseases. These findings increase the possibility that the active BAFF/APRIL heterotrimer may play a role in rheumatic diseases and other autoimmune diseases.