Though technologies for isolating and analyzing CTCs have advanced rapidly, there has been little clinical uptake of these technologies, despite the potential to assist medical decision-making. The first clinical studies examined the enumeration of CTCs and there were differing outcomes of utility; many of these studies were hampered by small sample sizes. More recent clinical studies have focused on molecular and genetic analysis of CTCs, rather than mere enumeration, to be utilized as a companion diagnostic to determine if a druggable mutation is present or absent (such as the T790M EGFR or V600E BRAF mutations). The rise of genetically targeted therapies has increased interest in CTC analysis in a clinical setting, particularly to obtain actionable information. CTCs hold the potential to assist with clinical decision-making, though further controlled trials will be necessary to better realize this promise.