Glioblastoma (GBM) is an aggressive, high-grade glioma characterized by rapid growth and microvascular proliferation. Tumors are typically localized to the cerebrum and rarely distantly metastasize. Worsening of neurocognitive symptoms is observed with GBM progression, and can significantly impact patient function and quality of life. Current treatments are non-curative and have not demonstrated an increase in overall survival. Progression-free survival (PFS) is a common primary endpoint in clinical trials of GBM therapies; however, it is important in this patient population to quantify how time without disease progression benefits patients. Recent decisions by health authorities and payers suggest an increasing trend towards the need for evidence of patient-centered endpoints, particularly for reimbursement decision-making. Assessment of neurocognitive deterioration due to GBM progression during the clinical trial period is challenging given the need to sensitively assess a range of symptoms that may manifest due to lesions in different regions of the brain.  A disease model, or conceptual framework, is needed to ground decision-making around choice of instruments, endpoints, and schedules of symptom assessments, thus ensuring measurement of the most patient and biologically relevant symptoms. The framework presented here outlines the biological processes that contribute to non-focal symptoms of GBM, such as headache, as well as focal symptoms, such as visual disturbances, changes in memory, or loss of verbal expression.  Considerations and challenges in assessing neurocognitive symptoms in GBM patients utilizing existing tools and methodologies are reviewed and identified.