Many autoimmune diseases, including systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and Sjogren’s disease (SjD), exhibit a female bias, with more than 80% of patients being female 1, 2, 3. While it is well established that sex differences in immunologic responses and disease can arise from sex hormones (reviewed elsewhere [4]), pathways involving the X chromosome have been gaining more recent attention. For example, epidemiological studies revealed that individuals with two or more X chromosomes are at higher risk for developing SLE 5, 6, SSc [7], or sJD [8], and males with Klinefelter’s syndrome (XXY) have a similar risk of developing these female-biased autoimmune diseases compared to females (XX). These observations suggest that having multiple X chromosomes contributes to female-biased autoimmune disease susceptibility. Female mammals with more than one X chromosome (XX) equalize X-linked gene expression to that of males (XY) via X Chromosome Inactivation (XCI), a developmental process in which one X chromosome is randomly chosen for transcriptional silencing [9]. The X chromosome is highly enriched in genes that regulate the immune system. As such, potential defects in XCI could lead to altered expression of these X-linked genes and promote autoimmunity. XCI is initiated and maintained by the long noncoding RNA XIST/Xist, an RNA that is not translated (reviewed in Ref. [10]) and functions through its interactions with the inactive X chromosome (Xi) and numerous interacting proteins. Recent studies have implicated both XIST/Xist RNA and XIST/Xist RNA-protein complexes in driving female-biased autoimmune disease. In this review, we summarize recent advances in our understanding of XCI maintenance mechanisms in lymphocytes and novel proposed roles for the X-linked long noncoding RNA XIST/Xist in female-biased SLE.