Obtaining diagnostic specimens, notably to monitor disease course in cancer patients undergoing therapy, is an emerging area of research, however, with few clinical implications so far in the field of Neuro-oncology. Specifically for patients with primary brain tumors where repeat biosampling from the tumor and clinical decision making based on neuroimaging alone remain challenging, this area may assume a central role. In principle, sampling could focus on blood, cerebrospinal fluid or urine with differential sensitivities and specificities of findings that differ between specific parameters and target molecules. These include protein, mRNA, miRNA, cell-free DNA, either freely circulating or as cargo of extracellular vesicles, as well circulating tumor cells. The most solid biomarkers are those directly reflecting neoplastic disease, e.g., in the case of primary brain tumors isocitrate dehydrogenase mutation or epidermal growth factor receptor variant III. Importantly, the main goals of liquid biopsy marker development are to better understand response to therapy, natural evolution and emergence of resistant clones, rather than obviating the need for surgical interventions which remain to be a mainstay of therapy for the vast majority of primary brain tumors.