The number of human conditions that are currently considered to be autoimmune 
diseases (AID) has been steadily growing over the past decades and it is now 
estimated that over 10 million people are affected in the United States. One of 
the major shared features among AID is the predominance in the female sex which 
in some cases changes with the age at disease diagnosis. Numerous hypotheses 
have been formulated based on intuitive scientific backgrounds to justify this 
sex imbalance, i.e. sex hormones and reproductive factors, fetal microchimerism, 
other sex-related environmental factors, a skewing of the X-chromosome 
inactivation patterns, and major defects in sex chromosomes. Nevertheless, none 
of these hypotheses has thus far gathered enough convincing evidence and in most 
cases data are conflicting, as well illustrated by the reports on fetal 
microchimerism in systemic sclerosis or primary biliary cirrhosis. The present 
article will critically discuss the main hypotheses (loss of mosaicism, 
reactivation, and haploinsufficiency) that have been proposed based on findings 
in female patients with specific AID along with two additional mechanisms 
(X-chromosome vulnerability and X-linked polyamine genes) that have been 
observed in AID models. Further, recent data have significantly shifted the 
paradigm of X chromosome inactivation by demonstrating that a large number of 
genes can variably escape silencing on one or both chromosomes. As a result we 
may hypothesize that more than one mechanism may contribute to the female 
susceptibility to tolerance breakdown while the possibility that unknown factors 
may indeed protect men from AID should not be overlooked.