Systemic Lupus Erythematosus (SLE) is an autoimmune multi-organ disorder that has thousands faces of presentations. Its clinical course is extremely unpredictable, and these features make its diagnosis and treatment a real challenge for clinicians. It appears that the clinical course of SLE is determined by the genetic material, in combination with environmental factors. In this article, we have reviewed recent findings on SLE pathogenesis with genetics view, focusing on defects in clearance of apoptotic bodies and immune complexes, alterations in innate immune system response, and also impaired pathways in the adaptive immune system. Furthermore, the major histocompatibility complex (MHC) and non-MHC genes that were discovered by genome-wide association studies (GWAS) in SLE patients were also evaluated. Besides, the effect of these polymorphisms on the function of their related transcripts and their association with SLE clinical manifestations and its pathophysiology were explained. Finally, the correlation of genetic polymorphisms with clinical responses to common medications in SLE treatment was also discussed.