Recent advances in molecular biology and drug design have described novel targets in bladder cancer. EGFR, fibroblast growth factor receptor (FGFR), VEGFR, phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway, PD-1, cyclooxygenase 2 (COX-2), Aurora kinase A, and miRNA are just examples of these opening frontiers. In addition, epithelial to mesenchymal transition (EMT) and cancer stem cells (CSCs) are promising candidates for future therapeutic approaches. Novel agents, combination, and sequences are emerging from the 747 clinical studies presently in course in bladder cancer to optimize patient outcomes. This report describes the emerging targets and provides an update on ongoing phase I, II, and III trials and preliminary results on targeted agents, used alone, in sequences, or in combination for patients with bladder cancer.