The use of circulating tumor cells (CTCs) isolated from liquid biopsy are already used to predict disease progression and survival in metastatic patients. However, the lack of robust drug screening assays has hampered their application in monitoring patient drug response/resistance and personalized therapy decision. We have developed a workflow to isolate tumor cells from pleural effusion and malignant ascites samples from metastatic lung and breast cancer patients and subjected them to medium scale drug screens against approved anticancer drug libraries. This approach allows realization of personalized treatment decisions within less than a week by evaluating drug responses directly in patient-derived tumor cells obtained from liquid biopsy. In patients with no pleural effusion or malignant ascites, we have established another workflow to isolate viable CTCs from peripheral blood of metastatic patients, from which we have generated 2D and 3D in vitro (spheroids and organoids) and in vivo (CTC-derived xenografts) models. Particularly, drug screens on CTC-derived organoids was feasible within therapeutic timeframes which can potentially influence personalized treatment strategy. Drug responses from the screen mirrored patients’ drug resistance and revealed promising candidates for treatment of individual patients. Beyond that, high-throughput drug screens in CTC-derived preclinical models closely mimicking patients' setting enable discovery, repurposing and development of more efficient cancer therapeutics. Integration of drug screening of liquid biopsy-derived tumor cells constitutes a powerful tool to better improve personalized treatment strategies and discovery for metastastic patients.