Various theories have been promulgated to explain the pathogenesis of endometriosis. Interest in the genesis of the endometriotic lesion has been a focus since the earliest investigations. More recently, investigators have addressed aspects of the immune system and local peritoneal factors that may be involved with both the histogenesis of endometriosis as well as its sequelae. This review will consider evidence for different theories of histogenesis and will discuss our current understanding of the contribution of the immune system to the etiology of endometriosis. Data will be presented regarding recently described models of the early endometriotic lesion. The interaction of endometrial cells with the peritoneal mesothelium seems critical to our understanding the formation of the early endometriotic lesion. Evidence of rapid transmesothelial migration and invasion of the peritoneum will be considered. As well, candidate adhesion molecules that may facilitate the initial binding of endometrium to the peritoneum will be discussed.