Abstract Although radiologic imaging and histologic assessment of tumor tissues are classic approaches for diagnosis and monitoring of treatment response, they have many limitations. These include challenges in distinguishing benign from malignant masses, difficult access to the tumor, high cost of the procedures, and tumor heterogeneity. In this setting, liquid biopsy has emerged as a potential alternative for both diagnostic and monitoring purposes. The approaches to liquid biopsy include cell-free DNA/circulating tumor DNA, long and micro noncoding RNAs, proteins/peptides, carbohydrates/lectins, lipids, and metabolites. Other approaches include detection and analysis of circulating tumor cells, extracellular vesicles, and tumor-activated platelets. Ultimately, reliable use of liquid biopsies requires bioinformatics and statistical integration of multiple datasets to achieve approval in a Clinical Laboratory Improvement Amendments setting. This review provides a balanced and critical assessment of recent discoveries regarding tumor-derived biomarkers in liquid biopsies along with the potential and pitfalls for cancer detection and longitudinal monitoring.