<b><i>Background:</i></b> Liquid biopsy is a collective term that refers to the analysis of tumor-derived biomarkers isolated from biological fluids of cancer patients. Recently, many authors reported the usefulness of liquid biopsy for the management of malignancy. <b><i>Summary and Key Messages:</i></b> The peripheral blood of cancer patients is a pool of cells and/or cell products derived from the primary or metastatic tumor, including circulating tumor cells (CTCs), circulating free (cf) DNA or RNA, and exosomes containing proteins, nucleic acids, and lipids. CTCs are tumor cells that can be isolated from peripheral blood. Free circulating DNA with a tumor-specific mutation is called circulating tumor DNA (ctDNA). Some patients who undergo curative surgery experience recurrent disease, which can be due to the presence of minimal residual disease (MRD). Thus, MRD indicates a high risk of relapse. Detection of ctDNA or CTC after surgery is a direct proof of MRD. Molecular volume (e.g., the number of CTCs and level of ctDNA) might reflect tumor burden, thus high molecular volume may indicate poor prognosis. The most notable application of liquid biopsy in cancer is to understand spatial and temporal heterogeneities. Heterogeneity is one of the causes of refractoriness and hampers prediction of chemotherapeutic effect. Emerging mutations that are not present in primary tumors but are found in their metastases can be detected in ctDNA. Some colorectal cancer patients with wild-type <i>RAS</i> do not respond to epidermal growth factor receptor blockade. In a subset of these patients, <i>RAS</i> mutation is detected in ctDNA, indicating heterogeneity.