CD44, a multi-structural and multifunctional transmembrane glycoprotein, was initially identified as a receptor for hyaluronan that participates in both physiological and pathological processes. CD44 is found to be closely linked to the development of various solid tumors. Molecular studies have revealed that high CD44 expression was correlated with the phenotypes of cancer stem cells and epithelial-mesenchymal transition, thereby contributing to tumor invasion, metastasis, recurrence, and chemoresistance. Correspondingly, blockade of CD44 has been demonstrated to be capable of attenuating the malignant phenotype, slowing cancer progression, and reversing therapy resistance. Clinical analyses showed that high CD44 expression is associated with poor survival of various cancer patients, indicating that CD44 can be a potential prognostic marker. In this review, we summarize recent research progress of CD44 on tumor biology and the clinical significance of CD44.