Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by excessive production of a variety of autoantibodies, accumulation of immune complexes, and multiple organ systems involvement. Interleukin-10 (IL-10) has an important role in the growth, survival, differentiation, and function of B cells. Abnormally increased IL-10 synthesis seems contributing to the spontaneous hyperactivity of the B cell compartment, so that it can directly result in autoantibody production by committed plasma cells, circulating immune complexes formation, and eventually in tissue and organ damage, suggesting it might associate with the development of SLE. A better understanding of the regulation of IL-10 and its receptors (IL-10R) can likely provide more valuable clues to the pathogenic mechanisms underlying specific forms of SLE, so as to pave the way toward more effective therapeutics.