Standard cytotoxic regimens for metastatic bladder cancer, such as gemcitabine/cisplatin or methotrexate, vinblastine, doxorubicin, and cipslatin (M-VAC), yield impressive overall response rates of 45% to 70%. Despite this, long-term, disease-free, overall survival is rare, and most patients eventually succumb to the disease. Much work has been undertaken evaluating the clinical and molecular factors associated with progressive bladder cancer, and this has, in turn, led to the development of both novel targets and agents. These include standard cytotoxics such as pemetrexed, an antifolate and antimetabolite agent that has demonstrated an overall response rate of 30% in early studies, and small-molecule tyrosine kinase inhibitors such as sunitinib, which will be studied as maintenance therapy for patients who respond to first-line chemotherapy. The evaluation of new targets and new agents in the midst of limited patient, logistical, and financial resources will be one of the more difficult challenges for investigators over the next several years.