CD44 is a polymorphic integral membrane protein, which binds to hyaluronic acid (HA), and contributes to cell-matrix adhesion, cell proliferation, migration, and tumor metastasis. When the CD44 is transcribed, its pre-messenger RNA can be received alternative splicing and maturated into mRNAs that encode various CD44 isoforms. The mRNA assembles with ten standard exons and the sixth variant exon encodes CD44v6, which plays critical roles in cell proliferation, migration, survival, and angiogenesis. Functionally, CD44v6 can interact with HA via the standard exons-encoded region. Furthermore, the v6-encoded region functions as a co-receptor of various receptors for epidermal growth factor, hepatocyte growth factor, C-X-C motif chemokine 12, and osteopontin. Therefore, the receptor tyrosine kinase or G protein-coupled receptor signaling pathways are potentiated in the presence of CD44v6. These functions are essential for homeostasis or regeneration in normal tissues. Importantly, CD44v6 overexpression plays a critical role in CRC progression. For instance, CD44v6 is involved in colorectal carcinoma invasiveness, colonization, and metastasis. Therefore, CD44v6 is a promising target for cancer diagnosis and therapy.