Endometriosis was first described by Carl von Rokitansky in 1860, but to date, over 150 years later, endometriosis remains an enigmatic disease. Its pathophysiology, diagnosis and medical treatment continue to challenge basic and medical scientists alike. We do know that endometriotic lesions derive from the ability of menstrual endometrial fragments to attach and implant on the peritoneum. This is supported by the clinical experience that endometriotic lesions are primarily associated with women of reproductive age and are composed of epithelial well as stromal cellular compartments, although the possibility that metaplasia in the peritoneum itself is also directly involved cannot be excluded. In terms of reproductive medicine, this is a chronic disease that can become painful and distressing for many women and give rise to a major loss in the quality of life. There are therefore strong incentives for continuing basic research. So, what are the main factors that limit successful treatment? First, is the difficulty of diagnosis. Up to now, there are no noninvasive diagnostic tools available for diagnosis. Only laparoscopic investigation provides a confirmed diagnosis of endometriosis and it takes on average 6 years following the beginning of the initial symptoms. A majority of women who suffer from subfertility get diagnosed with endometriosis within the context of IVF treatment by which time the disease has already developed into a chronic condition. Second, the medical treatment for endometriosis is primarily aimed at the suppression of ovarian function and hence menstruation through reducing the effect of estrogen on ectopic endometrial implants. However, in addition to the side effects of inhibiting ovarian function for an extended period of time, current treatment modalities only suppress the disease and do not prevent its recurrence and the associated symptomology upon cessation of treatment. Third, any new therapeutic approach has to factor-in that most women suffering from endometriosis are of reproductive age and still desire to have children. Drugs targeted to interfere with adhesion, invasion or persistence of the ectopic lesions need to ensure that they do not interfere with appropriate implantation and development of the embryo, always bearing in mind that this is a complex disease with multiple interactive components, including genetics, environmental risk factors as well as impaired hormonal responses. Moreover, the presence of lesions leads to inflammatory disorders that in turn can effect ovulation and hormone production as well as genetic changes in the ectopic endometrium, which could lead to subfertility. It is therefore a major challenge to design effective new therapies to target these complex mechanisms without interfering with the normal reproductive cycle and the potential for conception. In the ‘omic’ era, our enhanced understanding of the cell biology and molecular basis of endometrial function has opened up new opportunities to gain novel insights into the complex etiology of endometriosis and translate that knowledge into more effective treatment. With that in mind, this issue of MHR aims to survey the current status of the basic science of endometriosis. The complexity of this disease makes it impossible to cover all aspects of the ongoing research on endometriosis in one special issue. We therefore focus here on recent advances in understanding the etiology of endometriosis derived from genomic and proteomic analyses. Above all, the articles demonstrate some novel approaches to improving potential diagnosis and treatment modalities and highlight the value of different animal models for testing their effectiveness. We would like to express our profound gratitude to all the authors who contributed to this issue and agreed so spontaneously to publish their best work in this special issue. Their work and those of others will help us understand the pathophysiology of endometriosis which continues to elude us.