Based on the available scientific evidence, the mechanism of developing endometriosis appears to be transplantation of viable endometrial cell fragments shed during menses and regurgitated through the fallopian tubes under the influence of prostaglandin-mediated uterine contractions. As all women apparently retrograde menstruate to some extent, it is not surprising that circumstances which increase the total number of menstrual days experienced have been clinically associated with endometriosis. Similarly, factors which lead to relative uterine outflow obstruction have been associated with a higher incidence of endometriosis. There is virtually no other scientific evidence supporting alternate mechanisms of development of endometriosis. There are many unanswered questions regarding endometriosis including: 1) Are all women equally susceptible to development of the disease? 2) As the clinical presentation and course is extremely variable, what factors influence these events? 3) Does medical suppression of ovulation with oral contraceptives or continuous progestins provide a protective effect? 4) Are there systemic immunologic changes associated with endometriosis? Hopefully, this manuscript will help stimulate the next generation of clinical investigators to address these questions, as they are of paramount importance with this apparently increasingly devastating and frequent clinical disease.