Spontaneous or treatment-induced tumor lysis syndrome (TLS) can cause significant morbidity and potential mortality. Vigorous hydration, alkalinization and inhibition of uric acid synthesis with allopurinol are the most frequently used methods for treatment and prevention of TLS. However, this approach fails to prevent renal insufficiency in up to 25% of high-risk patients. With the increased intensity and efficacy of cancer therapies, novel approaches for the management of TLS are needed. Unlike allopurinol, urate oxidase promptly reduces the existing uric acid pool, prevents accumulation of xanthine and hypoxanthine and does not require alkalinization, facilitating phosphorus excretion. A recombinant form of urate oxidase, rasburicase, is now registered for the treatment and prevention of TLS. This review provides an overview of rasburicase development and discusses the impact of rasburicase in the prevention and management of TLS.