Context.-Pathologic diagnosis of tumors in the genitourinary system can be challenging based on morphology alone, particularly when diagnostic material is limited, such as in core biopsies. Immunohistochemical stain can be a useful tool to aid in the diagnosis. Objective.-To provide an update on practical applications and interpretation of immunohistochemical stains in the diagnosis of tumors in prostate, kidney, bladder, and testis. We particularly focus on difficult differential diagnoses, providing our insights in frequently encoun-tered challenging situations. Commonly used immunohistochemical panels are discussed. Data Sources.-Review of literature and our own experience. Conclusion.-Immunohistochemical stain is a valuable tool in the diagnosis of genitourinary tumors when appropriately used.