The clinical management of bladder cancer has seen little change over the last three decades and there is pressing need to identify more effective treatments for advanced disease. Low clinical use of neoadjuvant therapies stems from historical limitations in the ability to predict patients most likely to respond to combination chemotherapies. This article focuses on recent molecular and genetic studies, highlighting promising clinical trials and retrospective studies, and discusses emerging trials that use predictive biomarkers to match patients with therapies to which they are most likely to respond. The implementation of predictive genomic and molecular biomarkers will revolutionize urologic oncology and the clinical management of bladder cancer.