Accurate diagnosis of solid organ malignancies currently relies upon acquisition of a tissue sample directly from the tumor itself. While this method is the gold standard and typically provides enough tissue to perform histopathological, immunohistochemical, and molecular analysis, it does have several drawbacks. Depending on the disease location, tissue biopsies are relatively invasive. There may be technical challenges with biopsying anatomically remote locations as well as the potential for biopsy-related complications. Image-guided, endoscopic and surgical procedures are resource intensive and require substantial logistical input to arrange. In addition, a biopsy necessarily represents only a small fraction of the entire neoplastic process at a single timepoint. Spatial and temporal tumor heterogeneity not captured may nevertheless impact on the success of treatment protocols and targeted therapies. Liquid biopsy, the process whereby tumor fragments are detected in bodily fluids (typically blood), represents an easily accessible, minimally invasive alternative to formal tissue diagnosis. It also has prognostic value, both with respect to the absolute concentration detected at diagnosis, dynamic stratification based on response to treatment, and monitoring of development of treatment resistance. It also has the facility to extensively capture tumor heterogeneity. Various methods exist, most commonly based on analysis of circulating tumor cells or DNA fragments. Liquid biopsy has been utilized as a diagnostic and prognostic adjunct in a wide range of solid tumor types, including breast, prostate, pancreas, colorectal, and lung. Despite these advantages, liquid biopsy remains inferior to tissue biopsy for diagnostic sensitivity and specificity, especially for early-stage tumors. In clinical applications, it is unlikely that liquid biopsy will replace tissue biopsy for formal diagnosis, but is likely to have a significant role as a biomarker to assist with prognostication, development of treatment resistance, and early identification of disease recurrence.