Tumor cells detach from the primary tumor or metastatic sites and enter the peripheral blood, often causing metastasis. These cells, named Circulating Tumor Cells (CTCs), display the same spatial and temporal heterogeneity as the primary tumor. Since CTCs are involved in tumor progression, they represent a privileged window to disclose mechanisms of metastases, while -omic analyses at the single-cell level allow dissection of the complex relationships between the tumor subpopulations and the surrounding normal tissue. However, in addition to reporting the proof of concept that we can query CTCs to reveal tumor evolution throughout the continuum of treatment for early detection of resistance to therapy, the scientific literature has also been highlighting the disadvantages of CTCs, which hampers a routine use of this approach in clinical practice. To date, an increasing number of CTC technologies, as well as -omics methods, have been employed, mostly lacking strong comparative analyses. The rarity of CTCs also represents a major challenge, because there is no consensus regarding the minimal criteria necessary and sufficient to define an event as CTC; moreover, we cannot often compare data from of one study with that of another. Finally, the availability of an individual tumor profile undermines the traditional histology-based treatment. Applying molecular data for patient benefit implies a collective effort by biologists, bioengineers, and clinicians, to create tools to interpret molecular data and manage precision medicine in every single patient. Herein, we focus on the most recent findings in CTC -omics to learn how far we have come.