Tumor lysis syndrome (TLS) is an acute, life-threatening disease among adults and children that is associated with the initiation of cytoreductive therapy in the treatment of malignancy. A pattern of metabolic derangements occurs as a result of a massive release of intracellular contents into the systemic circulation. Characteristic findings include hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and uremia, all of which can lead to cardiac arrhythmia, seizures, renal failure, and sudden death. The incidence of TLS appears to be increasing because of a rapidly growing armamentarium of highly effective biologic and targeted therapies. Risk assessment and prevention are at the forefront of management and rely on clinician awareness, prophylactic measures, and vigilant laboratory monitoring. Established TLS requires early, aggressive intervention with intravenous hydration, electrolyte management, and the use of hypouricemic agents. This review highlights the central role of diagnostic laboratory criteria for TLS, and summarizes the clinical findings, pathophysiology, and evidence-based guidelines for the prevention and management of TLS.