An accurate profiling of the genomic landscape is mandatory to establish the best clinical and therapeutic approach for patients with solid malignancies. Moreover, tumor cells constantly adapt to external pressures-i.e., systemic treatment-with the selection and expansion of resistant subclones and the emergence of heterogeneous overlapping genomic alterations of resistance. The current standard for molecular characterization in cancer is the performance of a tissue tumor biopsy at the time of diagnosis and, when possible, a re-biopsy at the time of progression. However, tissue biopsy is not always feasible or practical and may underestimate tumor heterogeneity and clonal dynamics. Circulating DNA fragments carrying tumor-specific sequence alterations (circulating tumor DNA, ctDNA) are released from cancer cells into the bloodstream, representing a variable and generally small fraction of the total circulating cell-free DNA. Tumor genotyping in ctDNA (liquid biopsy) offers potential advantages versus the standard tumor tissue biopsy, including non-invasiveness and representation of molecular heterogeneity. Technical advances in sequencing platforms have led to dramatic improvements in variant detection sensitivity and specificity that allow for the detection and quantification of low levels of ctDNA. This provides valuable information on both actionable mutations and captures real-time variations in tumor dynamics. Liquid biopsy clinical applications include molecular diagnosis, determination of tumor load as a surrogate marker of early response, monitoring of mutations of resistance to targeted therapy and detection of minimal residual disease after cancer surgery. The aim of this chapter is to provide an overview of the biological rational and technical background of ctDNA analysis, as well as on the main clinical applications of liquid biopsy in dynamic treatment stratification in solid tumors. Special emphasis will be made on the current and potential benefits of the implementation of ctDNA in clinical practice, mainly in melanoma, lung, and colorectal cancer.