Tumor lysis syndrome (TLS) is an important metabolic disorder frequently encountered in the management of a variety of cancers including lymphoma, leukemia, and neuroblastoma. Delayed recognition can result in a variety of biochemical abnormalities resulting in life-threatening complications such as renal failure, arrhythmias, and seizures. Identification of high-risk patients and early recognition of the syndrome is crucial in the early institution of appropriate prophylaxis and treatment. Recent advances in the understanding of urate metabolism, development of new urate-lowering drugs, and the application of biomarkers, calculation methods, and prognostic models to identify high-risk patients will pave the way in improving the management of TLS. We included in this review the new information regarding the urate transporters URAT-1, organic anion transporter 1/3, and MRP4; the urate elimination pathway; a comparison of the old- (allopurinol, native uricase) and new- (febuxostat, Y-700, PEG-uricase, rasburicase) generation urate-lowering agents; and application of new biomarkers (cystatin-C, neutrophil gelatinase-associated lipocalin, kidney injury molecule 1), estimated glomerular filtration rate and calculation methods (modification of diet in renal disease and prognostic model (Penn Predictive Score of Tumor Lysis Syndrome) in the identification of high-risk patients, and alternative unexplored mechanisms (asymmetric dimethylarginine and adenosine) to explain renal injury related to TLS.