Circulating tumor cells (CTCs) represent an important biological link in the spread of primary solid tumors to the metastatic disease responsible for most cancer mortality. Their detection in the peripheral blood of patients with many different carcinomas has shown that tumor-cell dissemination can proceed at an early stage of tumor development and their presence is associated with poor clinical outcomes, particularly in metastatic disease. In this article we describe how the increasingly sensitive isolation and detailed molecular characterization of CTCs has greatly improved our understanding of metastatic proliferation. We focus on how CTC detection and knowledge of the molecular architecture of these cells can serve as biomarkers to signal metastasis-capable disseminating cells and predict therapy-specific response. This has marked clinical utility for improved selection of systemic therapies to the individual needs of a cancer patient, real-time monitoring of metastatic disease treatments and the development of new targeted therapies.