Hematogeneous tumor cell dissemination is a key step in cancer progression. The detection of CTCs in the peripheral blood of patients with solid epithelial tumors (e.g., breast, prostate, lung and colon cancer) holds great promise, and many exciting technologies have been developed over the past years. However, the detection and molecular characterization of circulating tumor cells (CTCs) remain technically challenging. The identification and characterization of CTCs require extremely sensitive and specific analytical methods, which are usually a combination of complex enrichment and detection procedures. CTCs occur at very low concentrations of one tumor cell in the background of millions of normal blood cells and the epithelial-mesenchymal plasticity of CTCs can hamper their detection by the epithelial markers used in current CTC assays. In the present review, we summarize current methods for the enrichment and detection of CTCs and discuss the key challenges and perspectives of CTC analyses within the context of improved clinical management of cancer patients.