Differentiation therapy for tumors refers to treating malignant tumors via the induction of cell differentiation. The best characterized clinical application of differentiation therapy is the use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia (APL), which markedly improved the outcome of this disease. Unlike the situation with APL, the development of differentiation therapy for solid tumors is far from satisfactory. To date, no differentiation-inducing agents have been demonstrated to exert a curative effect on solid tumors. However, over the past decade progress in understanding the differentiation pathways and the development of differentiation-inducing agents might shed new light on the differentiation therapy for solid tumors.