Clinically, superficial tumors (stages Ta, Tis, and T1) account for 75% to 85% of bladder neoplasms, while the remaining 15% to 25% are invasive (T2, T3, T4) or metastatic lesions at the time of initial presentation. More than 70% of patients with superficial tumors will have one or more recurrences after initial treatment, and about one third of those patients will progress and eventually die of the disease. New methods are needed to identify and monitor patients presenting with "high-risk" superficial tumors likely to develop into invasive carcinoma. Once invasive into muscle, the natural history is quite variable but highly lethal. Despite aggressive surgical resection, radiotherapy, and/or chemotherapy, the overall cure rate remains in the range of 20% to 50%. New biological determinants are needed both for proper selection of therapy and monitoring. In this review, we describe and update molecular alterations reportedly associated with bladder tumorigenesis and cancer progression. We also review novel genes and "signaling networks" identified by the use of high-throughput technologies. The concept of alterations affecting "genetic pathways" is becoming more than just a molecular biology exercise. The challenge is to evaluate such targets for therapeutic development, as well as to translate progression and outcome biomarkers into improved clinical management. Integration of data generated from in-depth clinical evaluation, histologic tumor characteristics, and validated biomarkers could provide highly accurate, predictive tools for management of the bladder cancer patient.