Treatment selection for patients with cancer often is based on characteristics that are inferred from their primary tumor. However, recent literature highlights the tendency of tumor cells to evolve dynamically along disease progression, suggesting that metastatic lesions may carry dramatically different drug sensitivity profiles. In patients, CTCs are direct derivatives of both primary and metastatic lesions and in this context, they represent an outstanding opportunity to improve clinical decision-making for patients with aggressive cancers, particularly those in whom metastasis tissue biopsies are challenging and survival chances are dismal.