The production of two regulators of the inflammatory response, interleukin 10 (IL-10) and tumor necrosis factor alpha (TNFalpha), has been found to be deeply deregulated in SLE patients, suggesting that these cytokines may be involved in the pathogenesis of the disease. Genetic polymorphisms at the promoter regions of IL-10 and TNFalpha genes have been associated with different constitutive and induced cytokine production. Given that individual steady-state levels of these molecules may deviate an initial immune response towards different forms of lymphocyte activation, functional genetic variants in their promoters could influence the development of SLE. The present review summarizes the information previously reported about the involvement of IL-10 and TNFalpha genetic variants on SLE appearance, clinical phenotype, and outcome. We show that, in spite of the heterogeneity of the populations studied, the existing knowledge points towards a relevant role of IL-10 and TNFalpha genotypes in SLE.