Spontaneous or treatment-induced tumor lysis syndrome (TLS) can cause significant morbidity and potential mortality. Vigorous hydration, alkalinization and inhibition of uric acid synthesis are the most frequently used methods for prevention of TLS. However, this approach requires hospitalization and tedious nursing care, and fails to prevent renal insufficiency in up to 25% of high-risk patients. With increased intensity and efficacy of cancer therapies, and the current trend to deliver treatment in the outpatient setting, novel approaches at 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 available. In this chapter we will present an overview of rasburicase development and discuss the impact of rasburicase in the prevention and management of TLS.