Cluster of differentiation 44 (CD44) is a glycoprotein receptor for hyaluronic acid, which plays a fundamental role in cellular adhesion, stromal binding, migration, and cell-cell interactions. Studies have suggested that the CD44-hyaluronate interaction is central to tumor invasiveness. Positive staining with Anti-CD44 is implicated in a multitude of different cancer types, including breast, prostatic, renal cell, colonic, hepatocellular, and genitourinary carcinomas, as well as Non-Hodgkin’s Lymphoma, metastatic melanoma, gastric cancer, and some soft tissue tumors. It has also been demonstrated that there is a positive correlation between tumor progression and increased expression of CD44v, a high molecular weight CD44 isoform that has been described in epithelial cells. Given the expression of CD44 in a wide range of cancers, the most practical application of CD44 immunostaining is its use in discriminating between urothelial transitional cell carcinoma in situ from non-neoplastic changes in the urothelium.