Endometriosis is a common gynecological condition that affects women in their reproductive years, and can lead to painful symptoms and infertility. The actual prevalence of the disease is unknown and its epidemiology is rather difficult to determine precisely as it requires surgery for diagnosis. However, in the year 2005, there were 1.67 billion women aged 15 to 49 years in the world. Assuming a1% prevalence means that there could be 16 million women with endometriosis worldwide; whereas a 20% prevalence implies there are 334 million women with endometriosis. Endometriosis is still an enigma and deciding on the optimal treatment for a patient can be very difficult for several reasons. First, there is no complete understanding of the etiology of the disease or its development or recurrence. Second, the pathophysiology leading to the pain and infertility associated with endometriosis is still not completely clear. Third, not only the mechanism(s) by which pain is caused are not fully understood, the link between the pain experienced and the extent of endometriosis is not well recognized. And even when endometriosis is diagnosed, it may not be the cause of a woman’s painful symptoms. Finally, although the severity of symptoms and the probability of diagnosis increase with age, peaking at about age 40 years old, the severity of pain experienced does not always directly correlate with the severity of endometriosis. Despite lack of evidence confirming the relationship between Nonsteroidal anti-inflammatory Drugs (NSAIDs) and endometriosis, NSAIDs are commonly prescribed treatments for endometriosis-related pain. This chapter will attempt at elucidating the relationship between endometriosis, prostaglandins and the logic behind treatment with NSAIDs. It will also shed some light on the available evidence-based modalities of treatment using cyclooxygenase (COX) inhibitors.