Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by the formation of a variety of autoantibodies and subsequent development of severe glomerulonephritis. Etiology of SLE remains unknown even if it is now well established that SLE is under polygenic control as well as the contribution of hormonal and environmental factors. The availability of several murine strains that spontaneously develop an autoimmune syndrome resembling human SLE, such as New Zealand, MRL and BXSB mice has provided useful tools for the genetic dissection of susceptibility to SLE. Moreover, development of various transgenic and mutant mice has made it possible to identify a number of susceptibility genes such as those involved in the regulation of apoptosis or B cell receptor signaling that can trigger lupus-like phenotypes. Obviously, further identification of the genetic defects present in lupus-prone mice is of paramount importance for understanding the immunopathogenesis of SLE.