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One of the most promising developments in translational cancer medicine has been the emergence of circulating tumor cells (CTC) as a minimally invasive multifunctional biomarker. CTCs in peripheral blood originate from solid tumors and are involved in the process of hematogenous metastatic spread to distant sites for the establishment of secondary foci of disease. The emergence of modern CTC technologies has enabled serial assessments to be undertaken at multiple time points along a patient's cancer journey for pharmacodynamic (PD), prognostic, predictive, and intermediate endpoint biomarker studies. Despite the promise of CTCs as multifunctional biomarkers, there are still numerous challenges that hinder their incorporation into standard clinical practice. This review discusses the key technical aspects of CTC technologies, including the importance of assay validation and clinical qualification, and compares existing and novel CTC enrichment platforms. This article discusses the utility of CTCs as a multifunctional biomarker and focuses on the potential of CTCs as PD endpoints either directly via the molecular characterization of specific markers or indirectly through CTC enumeration. We propose strategies for incorporating CTCs as PD biomarkers in translational clinical trials, such as the Pharmacological Audit Trail. We also discuss issues relating to intrapatient heterogeneity and the challenges associated with isolating CTCs undergoing epithelial-mesenchymal transition, as well as apoptotic and small CTCs. Finally, we envision the future promise of CTCs for the selection and monitoring of antitumor precision therapies, including applications in single CTC phenotypic and genomic profiling and CTC-derived xenografts, and discuss the promises and limitations of such approaches. See ALL articles in this CCR focus section, "Progress in pharmacodynamic endpoints."