Simple Summary: The search to identify and understand proteins which are strongly associated with cancer is critical to our abilities to treat the disease. CD44 is a protein which is known to be strongly associated with cancer progression. While the precise role that CD44 plays in cancer development and resistance to chemotherapy agents remains to be fully determined, the protein provides three avenues for possible novel therapeutic approaches. First, since CD44 is found on the surface of cancer cells, it is more accessible to the therapeutic agents which block its ability to carry out its negative functions. Second, since CD44 binds a sugar moiety called hyaluronic acid, chemotherapy agents can be packaged with hyaluronic acid so that they preferentially bind cancer cells with high levels of CD44 on their surface, resulting in a greater efficacy in treatment. Third, the levels of CD44 can be assessed in urine voided from bladder cancer patients, possibly informing on the aggressiveness or stage of the cancer without the need for invasive testing. All told, CD44 protein provides a number of opportunities to better monitor and therapeutically target cancer and deserves increased resources to further clarify this potential. The glycoprotein CD44, with its many isoforms and variations in carbohydrate patterning, participates in a diverse set of cellular functions. This fact leads to the protein playing a role in many normal and pathologic cellular processes including a role in cancer progression and metastasis. These same facts make CD44 a strong therapeutic target in many cancer types, including bladder cancer. [ABSTRACT FROM AUTHOR]