Human lupus is strongly associated with a gene expression signature characterized by over-expression of Type I interferon-regulated genes. A strong interferon signature generally is not seen in the standard mouse models of lupus, despite considerable evidence for the involvement of toll-like receptor-driven interferon production. In contrast, pristane-induced lupus exhibits a prominent TLR7-dependent interferon signature. Importantly, genetic disorders with dysregulated interferon production in both human beings and mice cause severe autoinflammatory diseases but not the typical manifestations of lupus, suggesting that interferon over-production is insufficient to cause systemic lupus erythematosus itself. Single-gene models in mice suggest that lupus-like disease may result from abnormalities in B-cell activation and the clearance of dead cells. Pristane may mimic human systemic lupus erythematosus by causing synergistic abnormalities in interferon production along with defective clearance of apoptotic cells and over-active B-cell signaling.