The largest difficulty one faces in the development of technology for detection of circulating tumor cells (CTCs) is whether or not tumor cells are present in the blood and at what frequency. Although the introduction of the validated CellSearch system for CTC enumeration has facilitated CTC research the question remains whether CTC are missed or whether the CTC that are reported are indeed clinically relevant. To fulfill the promise of CTC as a real-time liquid biopsy they will need to be present in the blood volume tested and need to be isolated without losing the ability to test the presence of treatment targets. To characterize a sufficiently large number of CTCs in the majority of cancer patients the volume of blood needed is simply too large to process without enrichment prior to detection. Here, we review the detection of CTCs by flow cytometry and fluorescence microscopy with and without immunomagnetic enrichment.