Tumor lysis syndrome (TLS) is a life-threatening oncologic emergency, characterized by a constellation of hyperkalemia, hyperuricemia, hyperphosphatemia, and hypocalcemia. The spectrum ranges from patients who are asymptomatic to those who go into cardiac arrest and die. Prompt recognition and initiation of treatment by emergency physicians are key, especially in the early stages of the syndrome. This case-based review presents an overview of the key points in pathophysiology, diagnosis, and management of TLS that are key to emergency physicians.