Papillary and invasive cancers of the urinary bladder appear to evolve and progress through distinct molecular pathways. Invasion in bladder cancer forebodes a graver prognosis, and these tumors are generally characterized by alterations in the p53 and retinoblastoma (RB) pathways that normally regulate the cell cycle by interacting with the Ras-mitogen activated protein kinase signal transduction pathway. Tumor angiogenesis further contributes to the neoplastic growth by providing a constant supply of oxygen and nutrients. Distinct epigenetic and genetic events characterize the interplay between the molecules involved in these pathways, thus affording their use as indicators of prognosis. Efforts are now underway to construct molecular panels comprising multiple markers that can serve as more robust predictors of outcome. While clinical trials for targeted chemotherapy for bladder cancer have commenced, novel genetic and pharmacologic agents that can target pathway-specific molecules are currently under development. The next generation of clinical management for urothelial carcinoma will witness the use of multimarker panels for prognostic prediction and combination therapy directed at novel molecular targets for treatment.