Systemic lupus erythematosus is a group of diseases that seem to become separate entities by etiology in the near future. Its pathogenesis remains elusive; however, multifactorial interactions among genetic and environmental factors may be involved. Systemic lupus erythematosus is the perfect prototype of autoimmune disorder with multiple derangements, starting from innate immunity to adaptive immune system leading to loss of self-tolerance. An overview of the pathogenesis of systemic lupus erythematosus is the focus of this review.