Autoimmune diseases are more prevalent in women while infectious diseases occur more often in men. Immune system responses differ between genders which suggest that sexual hormones are involved. Systemic Lupus Erythematosus (SLE) is an autoimmune disease with one of the greatest female sex bias. The etiology of the disease remains poorly defined. Gene-environment interactions are constantly being identified with epigenetics increasingly appearing as a crucial element in the pathogeneses of the disease. Sexual hormones are thought, for a long time, to be involved in the development of the disease given the sexual bias it presents. The monography pretends to evaluate estrogen’s role on the female SLE bias. As the predominant female hormone, and taking into account that the hormonal changes occurring in women relate to disease progression, it is a strong candidate to explain the higher women incidence and prevalence of the disease. Thought the female to male ratio is greater in the reproductive years it is still present in all ages. Other factors are probably rendering the female gender more susceptible to SLE, not ruling out estrogen as a large influent. Estrogen receptor a (ERa) emerges as a central player on immune system mediation by 17ß-estradiol (E2). Evidence on an aberrant cytokine profile on disease development is emerging and it seems to be dependent on ERa expression. The ER also modulates Toll-like Receptor (TLR) signalling and dendritic cells (DC) activity as does with B and T cells. These cells’s maturation and selection respond to E2 influence and their activity and survival are enhanced by its presence. TLR9 and minichromosome maintenance (MCM) proteins are also noteworthy as mediators of E2 action on immune cells. DNA methylation changes also involving ERa promoter region seem to participate in disease development. Different aspects of immune regulation can be modulated by the female hormone estrogen towards an increased system activation and reactivity. Other sexual hormones action on immune system should be studied in order to compare results and better understand the sexual bias in SLE.