The enhanced immunoreactivity in females is a double-edged sword that provides better protection against infections, but may lead to enhanced autoreactivity and thereby contribute to the induction of autoimmunity. Autoimmune diseases demonstrate a gender bias and represent the fifth leading cause of death by disease among females of reproductive age. Clinical and murine experimental studies indicate that the gender bias in autoimmunity may be influenced by sex hormones, predominantly displayed in the development and exacerbations of the prototypical autoimmune disease lupus. The associations between sex hormones and other autoimmune diseases are less clear. Our review on the impact of gender via sex hormones and sex related genes in the pathogenesis of several autoimmune diseases suggests that a better understanding of the underlying mechanisms behind the sexual dimorphism of the immune system may lead to the development of novel therapeutic approaches to autoimmunity.