Urothelial carcinoma is the second most common genitourinary malignancy. Although the majority of patients present with superficial bladder tumors, there are several clinical problems, such as progression to invasive tumors, poor prognosis of invasive tumors, and chemosensitivity. Alterations in p53 represent one of the most common genetic events in patients with invasive urothelial carcinoma and are suggested to be linked to tumor progression, prognosis, and chemosensitivity. p53 possesses various functions, including induction of cell-cycle arrest, apoptosis, DNA repair, and antioxidants; it acts as a killer and a healer. In this article, we review the roles of p53 pathways in bladder carcinogenesis and findings from recent studies of ours and other groups, and we discuss the clinical significance of the abrogation of p53 pathways in the treatment of urothelial carcinoma.