Systemic lupus erythematosus (SLE) is an autoimmune disorder affected by multiple genetic, hormonal and environmental factors, which makes it impossible to identify the exact cause of this ailment by only investigating SLE patients, who are genetically heterogeneous, and live in various environments. Therefore, the study of mouse models of lupus has provided valuable clues to help identify, and to validate, novel molecular pathways and targets implicated in the pathogenesis of the disease. While there is no perfect model to reflect all the disease phenotypes observed in human patients, disease subsets are represented in various animal models, which allows modulation of a particular pathophysiological pathway, resulting in the possibility of dissecting its specific contribution to disease development. Spontaneous mouse models of lupus have led to identification of numerous susceptibility loci, from which several candidate genes have been found, while induced models of lupus have provided insight into the role of environmental factors, as well as a better understanding of the cellular mechanisms by which SLE develops. Animal models also allow us to screen and evaluate potential preventive and therapeutic agents. Correlation of specific pathways in animal models to subsets of human disease offers the unique possibility of more accurate preclinical predictions of efficacy for single or combinatorial therapeutic approaches in the clinic. Here, we introduce various animal models of SLE, and review current data focused on genetic factors that are associated with susceptibility or phenotypes of lupus, leading into the present understanding of the genetic basis in lupus pathogenesis.