Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease of unknown etiology, characterized by the presence of widespread immunological abnormalities and multiorgan injury. An important advance over the past decade has been our understanding of how different genetic loci (or genes) may dictate specific immune abnormalities in lupus. "Genetic dissection" has unveiled some of the mystery enshrouding lupus pathogenesis. It appears that there are at least two distinct events leading to disease. The first involves a breach in the adaptive immune system and the second involves a dysregulation of innate immunity. Co-ordinate dysregulation of both checkpoints is necessary for full-blown lupus to ensue. The challenge ahead is to understand how these two checkpoints are regulated in human SLE, and to devise therapeutic strategies that target both checkpoints.