During the past 25 years, the incidence of ectopic pregnancy has progressively increased while the morbidity and mortality have substantially decreased, and the treatment has progressed from salpingectomy by laparotomy to conservative surgery by laparoscopy and more recently to medical therapy. This therapeutic transition from surgical emergency to medical management has been attributed to early diagnosis through the use of sensitive assays for hCG and the high definition of vaginal ultrasound. By using these sensitive diagnostic tools, we are now able to select those patients who are most likely to respond to medical management versus those who are at high risk of rupture and require surgery. Besides being less invasive and associated with significantly lower risks, medical therapy with methotrexate results in significant cost savings, which have been calculated to be approximately $3,000 per treated patient. Our goal is to identify those patients with ectopic pregnancy who are most likely to respond to methotrexate therapy and least likely to develop significant side effects. Recent studies have helped us define the predictors of success with methotrexate treatment in women with ectopic pregnancy. The reported success rates of treating ectopic pregnancy with methotrexate vary from 71% to 100%. The highest success rates have been reported from institutions that have detailed diagnostic and therapeutic protocols, readily available assays for serum hCG levels, high-resolution vaginal probe ultrasound, and support staff that can closely monitor clinical response. The importance of developing specific protocols to create a clinical environment that supports the effective use of medical therapy for ectopic pregnancy is confirmed by the associated cost savings, decreased morbidity, and patient preference. Modern diagnostic advances and minimally invasive treatments coupled with improved success rates for assisted reproductive technologies should reduce the morbidity and mortality associated with ectopic pregnancy and offer the affected couple a much more optimistic outlook for subsequent reproductive potential.