The evolution of technologies for the analysis of circulating tumor DNA (ctDNA) is opening important perspectives to revolutionize the approach to the diagnosis and treatment of patients with cancer. The availability of tests based not only on the identification of genetic alterations but also of non-genetic characteristics of ctDNA, such as methylation and fragmentation, has significantly increased the possibility of identifying ctDNA even in patients with limited disease. The ctDNA test provides important information on the prognosis of patients who are candidates for definitive therapy and could enable earlier diagnosis of cancer. The use of epigenetic markers allows a better interpretation of the results of tests performed in patients with metastatic disease. The new generation tests also allow for better monitoring of the response to therapy, which could represent an early endpoint in clinical trials with new drugs.