Primary brain tumors are associated with a poor prognosis and recognized impact on physical and neurologic function. In an effort to improve poor prognosis, novel therapeutic approaches have been pursued. The impact of therapy on function has not been fully evaluated in the past, with clinical trials focused on traditional survival endpoints. Therapies to date have been associated with incremental improvements in survival that may not have been associated with improvement in functional status. Methods for evaluating this impact include health-related quality of life symptom burden and evaluation of neurocognitive function. Each approach has associated benefits and limitations based on the type of treatment and the potential impact on functional status. An essential component of trial design evaluating functional endpoints is the development of clear hypotheses, specific aims, and predefined metrics of functional change related to each measure. This paper reviews these three approaches and discusses their potential use in evaluation of therapies for patients with primary brain tumors.