Glioblastoma (GBM) is the most common and devastating primary malignant brain tumor in adults. The past few years have seen major progress in our understanding of the molecular basis of GBM. These advances, which have contributed to the development of novel targeted therapies, will change the paradigms in GBM therapy from disease-based to individually tailored molecular target-based treatment. No validated circulating biomarkers have yet been integrated into clinical practice for GBM. There is thus a critical need to implement minimally invasive clinical tests enabling molecular stratification and prognosis assessment, as well as the prediction and monitoring of treatment response. After examination of data from recent studies exploring several categories of tumor-associated biomarkers (circulating tumor cells, extracellular vesicles, nucleic acids and oncometabolites) identified in the blood, cerebrospinal fluid and urine, this article discusses the challenges and prospects for the development of circulating biomarkers in GBM.