Systemic chemotherapy is the only current modality that provides the potential for long-term survival in patients with advanced or metastatic transitional cell carcinoma of the urothelium. The methotrexate/vinblastine/doxorubicin/cisplatin combination is currently considered to be the standard treatment of this disease, with overall response rates of up to 72% and survival durations of approximately I year. With the addition of gemcitabine to the chemotherapeutic arsenal, approaches to bladder cancer are changing significantly. When administered as a single agent, gemcitabine produces response rates of 23% to 28% in both pretreated and chemonaive patients with an excellent toxicity profile. When combined with cisplatin, overall response rates increase to 66% with maintained tolerability. Other new gemcitabine combinations with agents such as taxanes or carboplatin also appear promising; however, these preliminary phase II data must be confirmed in the phase III setting. Effective management of transitional cell carcinoma also involves understanding the mechanisms of resistance to treatment, including the implications of the expression of p-glycoprotein, p53 proteins, and several other biochemical predictors of outcome, as well as overcoming resistance. Growth factors may enable us to maximize drug delivery.