Transitional cell carcinoma is the second most common genitourinary malignancy in US and third most common cause of death among genitourinary tumors. Treatment options for bladder cancer include surgery, often combined with chemotherapy, radiation, and/or immunotherapy. The MVAC adjuvant chemotherapy regimen has been most widely used in locally invasive as well as metastatic disease. Only a proportion of patients at risk will respond to therapy. There is thus need to identify good responder patients for adjuvant therapy and to identify new targets to treat a greater range of patients. Based upon patient-specific aberrations in pathways or known markers, both existing and new therapies can be tailored to benefit patients based on the risk of progression and molecular alterations specific to a patient's tumor. Targeted therapy, therefore, is defined as therapy that targets mechanism and risk. Utilizing the available knowledge of the molecular biology of cell-cycle regulation, signal transduction, apoptosis, and angiogenesis in bladder cancer, we review the potential therapeutic targets for rational drug development. Finally, using bladder cancer as a model for translational research, requirements for a desired clinical trial are presented.