Systemic lupus erythematosus (SLE) is a complex autoimmune disorder in which 90% of patients are women. We suggest an X-chromosome dosage effect increases susceptibility to SLE. Our published data support this theory showing that men with Klinefelter’s syndrome (XXY) and trisomy women (XXX) are overrepresented in SLE by roughly 15- and 30–fold, respectively, compared to population and healthy controls. We hypothesize that X-linked genes escaping X-inactivation regulate immune responses. Based on lupus animal model studies, we propose X-linked genes that escape X-inactivation in both man and mice: DDX3X, KDM6A, KDM5C, EIF2S3, CXorf38, and CA5B, contribute to X-linked transcriptional dose differences. Preliminary data extracted from a publically available microarray dataset show that DDX3X and CXorf38 mRNA is increased in peripheral blood immune cells. Additionally, our group found that PBMCs had increased DDX3X protein in women compared to men. Potential connection of these genes to immune response, as well as, the preliminary data generated on DDX3X make a compelling case that these proteins are major contributors to, if not entirely responsible for, the X chromosome dosage effect and specifically the sex-bias observed in SLE.