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CD44 is an 80-95 kD glycoprotein that plays a role in various cellular functions including lymphocyte activation, recirculation and homing, hematopoiesis, and tumor metastasis. CD44 interacts with osteopontin, collagens, and matrix metalloproteinases (MMPs) and is a receptor for hyaluronic acid. Transcripts for this gene go through intricate alternative splicing that result in a variety of functionally distinct isoforms, including those which may be related to tumor metastasis. These splice variants of CD44 function as receptors under hemodynamic flow conditions that are significant to the development of cancer metastasis. Hence, it is thought that anti-CD44 tumor-specific mAbs may have therapeutic potential. This therapeutic potential of anti-CD44 mAbs is evident in some animal experiments demonstrating a reduction in malignant activities of various neoplasms when CD44 was targeted by a combination of mAbs, antisense oligonucleotides, and CD44-soluble proteins. It has been reported that high levels of CD44 on leukemic cells fuel leukemia production. Notably, various cancer studies show conflicting results pertaining to level of CD44 expression and its correlation with disease prognosis. Before anti-CD44 therapy can be applied to human cancers, it is essential to resolve this inconsistency.