Intravesical immuno- and chemotherapy, surgery, and systemic chemotherapy are all critical elements in our management of patients with bladder cancer. Despite our advances with these modalities, we continue to seek newer treatment paradigms to improve patient outcome. Targeted therapy with novel agents directed at specific molecular pathways is a promising avenue to achieve such progress. This manuscript is based on a talk given at the Spring Session of the Society of Urologic Oncology in May 2006. Here, we focus on targeting growth factors and their receptors in bladder cancer. In particular, we summarize our own and others' ongoing basic science, translational, and clinical research in this field. Foremost in this line of study is the epidermal growth factor receptor (EGFR)-targeted therapy with small molecule inhibitors and monoclonal antibodies. We discuss the rationale for EGFR-directed therapy in bladder cancer. The clinical efficacy has been disappointing, and extensive work has been done to characterize molecular markers for predicting response. Some of our own preclinical findings related to platelet derived growth factor-beta (PDGFR-beta) and some background on ongoing clinical trials targeting human EGF receptor 2 (HER2) are summarized. Fibroblast growth factor 3 (FGFR3) offers promise as a potential target for therapy of both superficial and invasive disease. The role of FGFR3 mutations in bladder cancer is reviewed. Finally, we discuss the targeting of VEGF. Ultimately, it may be the use of multi-kinase inhibitors or the combination of different inhibitors to various targets that yields the best results.