Molecular markers have potential as both diagnostics and predictors of progression and patient outcome in urothelial cancer. Advancements in technology have provided an understanding of the molecular mechanisms of carcinogenesis and defined distinct pathways in tumorigenesis and progression. Herein we present a select overview of the molecular underpinning of urothelial carcinogenesis and progression, and discuss the potential for some of the proteins involved in these processes to serve as biomarkers for evaluation of progression risk. Eventual refinement of prognostic methods with the addition of the latter markers will enable clinicians to provide an individualized therapeutic approach for each patient, and discover targets for novel therapeutic agents to disrupt the deregulation underlying the development and progression of urothelial carcinogenesis.