Circulating tumor cells (CTCs) are rare cancer cells shed from primary and metastatic tumors into the peripheral blood, and represent a “liquid biopsy” that may be performed repeatedly and non-invasively to monitor treatment efficacy and study tumor evolution during therapy. This approach is particularly relevant in metastatic prostate cancer, where the predominance of bone metastases limits the feasibility of tumor sampling using traditional biopsy. In collaboration with the MGH Bio MicroElectroMechanical Systems Resource Center and the MGH Cancer Center, we have developed microfluidic devices to efficiently isolate CTCs from peripheral blood of patients. We have used this novel technology to interrogate androgen receptor signaling status in prostate CTCs, to study the role of CTC clusters in metastasis, and to accomplish single cell RNA-seq of CTCs. Most recently, through comprehensive RNA-seq analysis of prostate CTCs, we demonstrated that activation of noncanonical Wnt signaling may contribute to anti-androgen resistance in prostate cancer. Ongoing research projects include the prospective evaluation of CTC-based biomarkers, the study of the molecular evolution of treatment resistance, and the development of “real-time precision medicine," integrating the genomic analyses of liquid biopsies and tissue biopsies to guide the personalized care of patients with prostate cancer.