The concept of liquid biopsy and the isolation and analysis of circulating biomarkers from blood samples is proposed as a surrogate to solid biopsies and can have the potential to revolutionize the management of patients with cancer. The relevance of circulating tumor cells (CTCs) and the importance of the information they carry is acknowledged by the medical community. But what are the barriers to clinical adoption? This review draws a panorama of the biological implications of CTCs, their physical and biochemical properties, and the current technological bottlenecks for their analysis in relation with the medical needs. Keys and considerations to bridge the technological and clinical gaps that still need to be overcome to be able to introduce CTCs in clinical routine are finally synthesized.