The cerebrospinal fluid (CSF) plays a critical role in maintaining homeostasis within the central nervous system (CNS). Detecting protein alterations in CSF associated with brain tumors offers a unique opportunity to enhance diagnosis, prognosis, recurrence monitoring, and treatment response. As an extracellular component of the CNS, it serves as a valuable reservoir of biomarkers that reflect changes associated with brain tumors—biomarkers that are often difficult to detect in the systemic circulation due to the blood-brain barrier. Advances in liquid biopsy techniques for CSF, coupled with high-throughput technologies, have the potential to significantly benefit patients. Here, we provide a comprehensive overview of methodologies for studying the CSF proteome to identify brain tumor-associated alterations.