Metastatic disease is the most common mechanism of death in patients with advanced bladder cancer. As for most solid tumors, chemotherapy remains the only realistic option for palliating or curing metastatic disease. However, bladder cancer is characterized by chemoresistance. Only modest response rates are obtained using multiagent regimens including cisplatin. These low response rates and the toxicity of these regimens limit their use to patients at highest risk. Here, we review the molecular mechanisms of cisplatin resistance. These include methods to reduce cisplatin bioavailability within a cell, and defects in the machinery that produces cell death following cisplatin-induced DNA damage. While overcoming these mechanisms is a potential therapeutic approach that can increase response rates, in the short term this knowledge could be used to predict response in individual tumors.