Liquid biopsy is a new diagnostic concept to investigate the molecular features of solid tumors by blood, saliva, urine, and any other body fluids which show a source of potential biomarkers. In cancer patients, it is a simple and less invasive mean, representing a sustainable alternative to interrogate all tumor cells longitudinally, quantifying and characterizing the biological materials (DNAs, RNAs, proteins) which originate from cancer tissues. Circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA) analysis from a simple blood draw received enormous attention for the related clinical research results. A rich scientific literature demonstrates that liquid biopsy is a valid instrument to assess the tumor biomarkers in real time and profile the cancer genotype in diagnostic and prognostic field, as well to quantify minimal residual disease, during patient follow-up. This could be a breakthrough for a companion diagnostic and personalized medicine. Liquid biopsy needs further implementation in the methodological aspects as well as cost-based assessment. The number of new molecular diagnostic assays increases day by day, but the standards for their adoption and clinical validation are still to be achieved.