Tumor lysis syndrome (TLS) is the most common onco-metabolic emergency occurring in both adults and children. It is triggered by breakdown of tumor cells either after cytotoxic therapy or spontaneously, resulting in release of large amounts of potassium, phosphate, and nucleic acids into the systemic circulation. TLS occurs when these metabolites overwhelm homeostatic mechanisms in the body leading to hyperkalemia, hyperphosphatemia, hyperuricemia, hypocalcemia, and their associated clinical manifestations. TLS can lead to acute kidney injury via crystal-dependent (uric acid and/or calcium phosphate crystal deposition in renal tubules) and crystal-independent mechanisms; cardiac arrhythmias and seizures, resulting in increased morbidity and mortality. TLS is commonly seen in high-risk hematologic malignancies such as Burkitt’s lymphoma and acute lymphoblastic leukemia but may also occur in highly proliferative and chemosensitive solid tumors. With the advent of novel therapies for a variety of hematologic and solid tumors including chimeric antigen receptor-T cell and tumor-infiltrating lymphocyte therapies, bispecific antibodies, and checkpoint inhibitors, the incidence of TLS is expected to increase. Identifying patients at risk and instituting prophylactic measures are key to minimize the clinical consequences of TLS. Management strategies include intravenous hydration to maintain high urine output, hypouricemic agents (rasburicase, allopurinol), close monitoring and correction of electrolyte abnormalities, and renal replacement therapy when indicated. In this chapter, we discuss the definition, diagnosis, epidemiology, pathophysiology, risk factors, clinical features, prophylaxis, and management of TLS, with an emphasis on high-risk patients who require intensive care support.