The expression of CD44 was upregulated in some hematological malignancies and is associated with metastasis and prognosis. The ligation of CD44 with specific monoclonal antibodies can trigger terminal differentiation of leukemic blasts in some subtypes, so it is probable to develop an anti-CD44 based differentiation therapy in leukemia. The effects of CD44 and its monoclonal antibodies are discussed in this review. The expression of CD44 was upregulated in some hematological malignancies and is associated with metastasis and prognosis. The ligation of CD44 with specific monoclonal antibodies can trigger terminal differentiation of leukemic blasts in some subtypes, so it is probable to develop an anti-CD44 based differentiation therapy in leukemia. The effects of CD44 and its monoclonal antibodies are discussed in this review.