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Detection of Circulating Tumor Cells (CTCs) in peripheral blood can serve as a "liquid biopsy" approach and as a source of valuable tumor markers. CTCs are rare, and thus their detection, enumeration and molecular characterization are very challenging. CTCs have the unique characteristic to be non-invasively isolated from blood and used to follow patients over time, since these cells can provide significant information for better understanding tumour biology and tumour cell dissemination. CTCs molecular characterization offers the unique potential to understand better the biology of metastasis and resistance to established therapies and their analysis presents nowadays a promising field for both advanced and early stage patients. In this chapter we focus on the latest findings concerning the clinical relevance of CTC detection and enumeration, and discuss their potential as tumor biomarkers in various types of solid cancers. We also highlight the importance of performing comparison studies between these different methodologies and external quality control systems for establishing CTCs as tumor biomarkers in the routine clinical setting.