A little more than half a century ago, young women were frequently dying of reproductive sequelae such as ectopic pregnancies and gestational trophoblastic disease. Mortality from these conditions was as high as 90 in the case of metastatic choriocarcinoma. If lives could be saved, it was in the operating theater and often at the expense of future reproductive potential. By the 1940s, however, targeted chemotherapy was starting to be explored, and the development of methotrexate for the treatment of childhood leukemia in 1949 eventually resulted in an unexpected, but nevertheless long and happy association with the field of gynecology. Here we trace the origins of methotrexate and how it came to be an effective medical treatment for two life-threatening gynecologic conditions. It illustrates how the contributions of many clinicians and scientists from many disciplines, over the greater part of a century, come together to improve the care of a single patient today.