The application of liquid biopsy approaches to diagnose cancer and to monitor treatment response has rapidly grown in the last 5 years. The liquid biopsy analysis provides an opportunity to obtain complementary molecular information from different bodily fluids (e.g., blood, urine, cerebrospinal fluid) that may allow for improved management of cancer patients. Apart from cytological and biochemical analysis of cerebrospinal fluid (CSF), the use of liquid biopsy as a diagnostic tool for central nervous system (CNS) metastases is still in its early stage. Identification and more extensive characterization of tumor cells and proteins, but also of circulating tumor DNA (ctDNA) and different forms of RNA in CSF, is increasingly pursued in order to improve the diagnosis and management of patients with CNS metastases. Furthermore, the utility of liquid biopsies for monitoring treatment responses of patients with CNS metastases is beginning to be explored. Although several challenges remain, current technological progress in assay development will allow to tackle limitations imposed by lack of standardized and validated methods for liquid biopsy-based diagnostics of CNS metastases. Inclusion of liquid biopsies in the design of longitudinal cohort studies with combined analysis of various liquid biopsy biosources is expected to advance the discovery of reliable molecular biomarkers for prediction and early detection of CNS metastases. As the result, novel treatment modalities may become available for patients at high risk of CNS metastases, preventing their future occurrence and thereby improving patient outcomes.