Numerous studies have been published since the early 1980s demonstrating alterations in the immune system or the immune response in endometriosis. In this chapter, we will discuss evidence provided by the literature as well as pertinent results from our own published studies which suggest a link between endometriosis and the immune system. Our approach to this topic comes from a theoretical perspective and, therefore, we do not cite exhaustively the full complement of relevant literature. Instead, the reader is directed towards the many excellent reviews, chapters and textbooks devoted to this subject. Our goal is to invite the reader to examine, ponder, and speculate what the evidence obtained from almost four decades of investigation tells us about this fundamental question: does the immune system cause endometriosis? we propose that there are genetic, epigenetic and functional factors, that are subject to forces in the external and internal environments of the human female, that can shift the balance of the immune system and the endometrium resulting in either establishment and progression or inhibition and spontaneous resolution of endometriosis.