Urothelial carcinomas demonstrate diverse morphologic and immunologic features that frequently lead to diagnostic challenges. Recent advances have identified a number of immunohistochemical stains that, when used in the context of a panel, can be a valuable tool in properly classifying primary urothelial carcinoma and carcinomas secondarily involving the urinary bladder. In addition, new biomarkers prove helpful in the staging of bladder carcinoma. In this article, we review the clinical utility of immunohistochemistry in a series of diagnostic scenarios, including flat urothelial lesions with atypia, rare variants of urothelial carcinoma, primary adenocarcinoma versus secondary colorectal tumors, distinguishing prostate from urothelial carcinoma, and the utility of smoothelin in staging bladder carcinoma. Emphasis is placed on panels of commonly used biomarkers to establish diagnoses.