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Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered circulation with potential to initiate a site of metastasis. Currently, CTC detection using CellSearch is cleared by the Food and Drug Administration for monitoring metastatic breast, prostate, and colorectal cancers as a prognostic biomarker for progression-free and overall survival. Accumulating evidence suggests CTCs have similar prognostic value in other metastatic and non-metastatic settings. Current research efforts are focused on extending the utility of CTCs beyond a prognostic biomarker to help guide clinical decision-making. These include using CTCs as a screening tool for diagnosis, liquid biopsy for molecular profiling, predictive biomarker to specific therapies, and monitoring tool to assess response and guide changes to treatment. CTCs have unique advantages vs circulating tumor DNA in this endeavor. Indications for CTCs in daily practice will expand as isolation techniques improve and clinical studies validating their utility continue to grow.