<p>Molecular pathological tumor diagnostics are becoming increasingly important in the context of personalized medicine. Modern high-throughput methods now enable routine molecular tumor profiling to identify genetic aberrations. Tissue biopsies are firmly established in routine clinical practice and remain the gold standard for initial diagnosis and are generally a&#xa0;prerequisite for tumor resection. They provide essential histological and immunohistochemical information; however, obtaining them can sometimes be difficult or involve risks and is often limited by the availability of tumor material. Furthermore, due to intratumoral heterogeneity, the entire spectrum of mutations is not always captured, which can influence the selection of targeted therapies. Against this backdrop, liquid biopsy is gaining importance as a&#xa0;minimally invasive, complementary approach. It enables the analysis of tumor-associated genetic alterations in circulating tumor DNA (ctDNA) and allows for repeated and systemic detection of molecular changes. For selected clinical questions, ctDNA analysis is already established in routine clinical practice, particularly for the identification of predictive markers and the detection of therapy-associated resistance mechanisms, for example in non-small cell lung cancer (NSCLC) or breast cancer. However, its widespread application is limited by methodological challenges, primarily due to the low amount of ctDNA and the resulting high demands on sensitivity and specificity. This is particularly true for early detection, which remains the subject of intensive research and controversial discussions. ctDNA-based therapy monitoring and the detection of minimal residual disease (MRD) represent promising approaches but require further prospective studies for standardization and integration into clinical guidelines. This review summarizes the possibilities, limitations, and available methods as well as current and potential applications of liquid biopsy in molecular diagnostics.</p>