A number of murine models recapitulate many of the features of systemic lupus. Spontaneous models of lupus have provided the basis for genetic linkage studies to define loci that confer an increased risk of nephritis in susceptible mice. Functional relevance of genes within susceptibility loci have been verified through the use of transgenic mice bearing targeted deletions or overexpression of candidate genes. Critical gene targets are involved in the production of autoantigens, stimulation of B cells to produce autoantibodies, stimulation of T cells to provide B cell help and cytokine-mediated damage following tissue deposition of immune complexes. In this overview, features of the commonly employed models of human lupus nephritis are reviewed. Strategies to identify candidate genes involved in the initiation and progression of lupus nephritis in these models are discussed. Finally, key studies to validate target genes as pathophysiologically relevant mediators of lupus nephritis and studies to identify potential targets for therapeutic intervention are summarized.