Historically disseminated tumor cells in solid cancers were detected by immunohistochemistry of bone marrow aspirates. Blood samples are more easily and frequently accessible and are therefore employed to detect circulating tumor cells (CTCs), a procedure termed “liquid biopsy”. CTCs are shed from tumors and a fraction of these cells is capable of establishing distal lesions. Since patients die from metastatic disease, CTCs hold potential to have prognostic significance and to indicate the success or failure of therapeutic interventions. With few exceptions, CTCs are rare cells against a large background of blood cells and need to be enriched for detection and characterization. The FDA-approved CellSearch© system relies on the selection of epithelial cell adhesion molecule (EpCAM)-positive tumor cells and is incorporated in numerous clinical studies for risk stratification and assessment of therapy. However, CTCs may have undergone (partial) epithelial-mesenchymal transition and are therefore missed by methods dependent on epithelial markers. A host of other techniques to enrich/isolate CTCs which are based on physical and/or distinct biological properties are under evaluation. Although single CTCs were linked to an increased risk of tumor progression, the actual phenotype and fraction of these cells capable of forming metastases are not known, as well as the mechanisms and kinetics of tumor cell shedding and evasion. Despite considerable progress, CTC detection methods still need to be validated and their clinical significance confirmed in larger multicenter trials before entering clinical routine practice.