Recent estimates suggest that autoimmune diseases cumulatively affect 5-10% of the general population worldwide. Although the etiology and pathogenesis remain poorly understood in most cases, similarities between diseases outnumber differences in the initiation and perpetuation of the autoimmune injury. One major example is the predominance of affected women, and perhaps its most intriguing putative mechanism is related to sex chromosomes, based on the recent observation that women with autoimmune diseases manifest a higher rate of circulating leukocytes with a single X chromosome. In a complementary fashion, there have been several reports on a role of X chromosome gene dosage through inactivation or duplication in autoimmunity. It is important not to overlook men with autoimmune diseases, who might manifest a more frequent loss of the Y chromosome in circulating leukocytes. Taken together, sex chromosome changes might constitute the common trait of autoimmunity.