<b><i>Background:</i></b> Despite the hype about circulating tumour cells (CTCs) in the early 2000s and their potential in the diagnosis of metastasis, in recent years, the hope for personalised cancer management relies more on circulating tumour (ct)DNA that has entered the clinic in a much more efficient way. So far, approved methods for CTCs in the clinic only provide the counting of CTCs, which enables monitoring of the progression of metastatic breast, prostate, and colorectal cancer patients with therapy. Approved methods for ctDNA facilitate the analysis of specific mutations in lung cancer, thereby providing indications for potentially successful treatments. This situation inclined the balance towards molecular analysis in liquid biopsy, leveraged by new technologies and companies providing broader mutation and gene expression analysis towards the early diagnosis of cancer. <b><i>Study Design:</i></b> We conducted a search for the studies published to date that provide details about the significance of CTCs in the clinic. <b><i>Results:</i></b> Many studies and clinical trials have demonstrated the potential of CTCs in patient screening, early diagnosis, therapy resistance, and patient prognosis. <b><i>Conclusions:</i></b> Large multi-centre studies are still needed to formally validate the clinical relevance of CTCs. Meticulous design of the clinical trials is a crucial point to achieve this long-sought objective.