Abstract Clinical research for patients with rare cancers has been very challenging. First and foremost, patient accrual to clinical trials typically requires a network, cooperative group, or even international collaboration in order to achieve the necessary numbers of patients to adequately evaluate a new treatment or intervention. Similar limitations in preclinical models and in the understanding the natural history of the disease or pertinent prognostic factors further impede the development of hypothesis-based, appropriately powered clinical trials. However, despite these challenges, several studies in rare cancers, including ependymoma and subependymal giant cell astrocytoma, have helped to establish new treatment regimens. Importantly, in these seminal trials, patient outcomes measures were critical in describing the clinical benefit derived from the therapy, underscoring the need to incorporate these measures in future trials. While obstacles still remain, novel and creative approaches to clinical trial designs have been developed that can be used to study new treatments for patients with rare cancers, thereby addressing a significant unmet need.