Despite the widespread use of surgery as a standard of care for tenosynovial giant cell tumor (TGCT), several therapeutic challenges remain, particularly in the setting of diffuse TGCT, where recurrent and difficult-to-treat disease can be present. In this activity, an orthopedic surgeon and medical oncologist debate the case-based management of challenging TGCT presentations, and illustrate the nuances of multidisciplinary collaboration when managing patients with TGCT. Throughout, the panelists profile a modern management synthesis that combines surgery, physical therapy, and the use of targeted agents, including for patients for whom surgery alone is unlikely to be beneficial.