Abstract: As a widely expressed cellular adhesion molecule, type I transmembrane glycoprotein CD44 is crucial in cell proliferation, differentiation, migration, angiogenesis and other biological processes to induce intracellular signal transduction and regulate tissue homeostasis. Especially, cell adhesion dynamics mediated by CD44-selectin and CD44-hyaluronic acid (HA) interactions play key roles in classic inflammatory cascade, tumor metastasis, or tissue-specific liver immunity. This review discussed the progresses and remaining issues of CD44 selectin and CD44-HA interactions in various aspects of cellular adhesion dynamics, two- and three-dimensional molecular reaction kinetics, atomic microstructural features, and intracellular signal transduction pathways. Nowadays, the importance of mechanical and physical factors to biological activities has been gradually accepted by scientific community. New concepts such as mechanomedicine, mechanoimmunology and mechanomics have been put forward one after another. Under physiological or pathological conditions, cell adhesion mediated by CD44-ligand interactions are regulated by in vivo mechanical and physical cues such as blood shear or tissue stiffness, but their regulatory mechanisms are still unclear. From that on, future perspectives related to CD44-ligand interaction were also proposed in this review as follows: how mechanical and physical factors regulate cellular adhesion dynamics and intrinsic mechanism mediated by CD44-ligand interactions; what the mechanical regulation features of molecular reaction kinetics of CD44-ligand interactions and corresponding structural bases are; and how the atomic-level microstructures of CD44-ligand binding evolve dynamically under mechanical forces. This review provides clues for further understanding the biological functions and structure-function relationship of CD44-ligand interactions.