CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, adhesion, migration, homing, and differentiation. This review focuses on the impact of CD44s/CD44v as biomarkers in leukemia development and discusses current research and prospects for CD44-related interventions in clinical application. CD44 is a transmembrane glycoprotein with molecular diversity produced by alternative splicing and post-translational modifications. It interacts with ligands like hyaluronic acid (HA) and osteopontin (OPN), mediating cell adhesion and signaling pathways. CD44's role in migration involves interactions with actin cytoskeleton proteins and signaling molecules like PKC, c-Src, and RhoGTPase. CD44 also regulates growth, proliferation, and survival through various signaling pathways, including PI3K-Akt and MAPK. Proteolytic cleavage of CD44 generates signaling molecules that activate transcription. CD44 is overexpressed in leukemia cells, correlating with chemoresistance, proliferation, and anti-apoptosis. CD44-targeted drugs, including monoclonal antibodies and small molecule compounds, are being developed to inhibit CD44-mediated processes. Natural compounds and chemotherapeutic drugs can also reduce CD44 expression, indirectly inhibiting leukemia stem cells. sCD44 and HA oligomers are potential therapeutic targets. CD44's role in the hematopoietic niche and immune escape mechanisms is discussed, highlighting its importance in leukemia treatment. HA-directed targeting of cancer cells using HA-modified nanoparticles and nanogels is a promising approach for targeted therapy.CD44 is a ubiquitous leukocyte adhesion molecule involved in cell-cell interaction, adhesion, migration, homing, and differentiation. This review focuses on the impact of CD44s/CD44v as biomarkers in leukemia development and discusses current research and prospects for CD44-related interventions in clinical application. CD44 is a transmembrane glycoprotein with molecular diversity produced by alternative splicing and post-translational modifications. It interacts with ligands like hyaluronic acid (HA) and osteopontin (OPN), mediating cell adhesion and signaling pathways. CD44's role in migration involves interactions with actin cytoskeleton proteins and signaling molecules like PKC, c-Src, and RhoGTPase. CD44 also regulates growth, proliferation, and survival through various signaling pathways, including PI3K-Akt and MAPK. Proteolytic cleavage of CD44 generates signaling molecules that activate transcription. CD44 is overexpressed in leukemia cells, correlating with chemoresistance, proliferation, and anti-apoptosis. CD44-targeted drugs, including monoclonal antibodies and small molecule compounds, are being developed to inhibit CD44-mediated processes. Natural compounds and chemotherapeutic drugs can also reduce CD44 expression, indirectly inhibiting leukemia stem cells. sCD44 and HA oligomers are potential therapeutic targets. CD44's role in the hematopoietic niche and immune escape mechanisms is discussed, highlighting its importance in leukemia treatment. HA-directed targeting of cancer cells using HA-modified nanoparticles and nanogels is a promising approach for targeted therapy.