CD44 is a cell surface receptor that recognizes multiple ligands (e.g., hyaluronan), acting as a cell adhesion molecule. CD44 is a type I transmembrane glycoprotein consisting of three main regions, i.e., an extracellular domain, a transmembrane domain, and a short cytoplasmic domain of approximately 70 residues (Fig. 100.1). The extracellular domain contains a link module that corresponds to a hyaluronan binding site. Following cleavage of the transmembrane domain by γ-secretase, the cytoplasmic domain translocates into the nucleus and contributes to transcriptional regulation. By interacting with the ligand, the cytoplasmic domain promotes actin cytoskeleton rearrangement via actin-binding proteins, thereby promoting cell migration and lymphocyte homing. CD44 interaction with hyaluronan is involved in cancer cell proliferation, survival, migration, invasion, metastasis, chemoresistance, and cancer stem cell properties [1, 2]. Moreover, CD44 functions in the internalization and degradation of cell surface hyaluronan, acting as a co-receptor for growth factor receptors. The CD44 gene comprises 20 exons. CD44 variant isoforms (CD44v) with altered extracellular domain structures are generated by the alternative splicing of exons 6–15 (Fig. 100.1). The CD44 standard form (CD44s), which lacks the variant region, is widely expressed from the fetus to adults. Multiple CD44v isoforms are expressed in cancer cells, and their expression is associated with tumor types, metastatic status, and prognosis.