Perhaps the most important advance in this field is not the specific actions of all-trans-retinoic acid in acute promyelocytic leukemia, but rather the conclusive documentation of differentiation as a practical and consistently effective method of treating human cancer. As a drug, all-trans-retinoic acid has certain undesirable pharmacologic properties that might be overcome by the use of alternative retinoids, such as 9-cis-retinoic acid, that are equally active against acute promyelocytic leukemia cells in vitro. In addition to retinoids that selectively activate RARs or RXRs, other ligands of the steroid-thyroid receptor superfamily, such as vitamin D3, glucocorticoids, and sex steroids also have cytodifferentiating actions in model systems. Numerous other agents can effect differentiation of neoplastic cells in such systems, including sodium butyrate, hexamethylene bisacetamide and its analogues, colony-stimulating factors, and interferons. Each of these compounds apparently acts through different pathways, and their activity may be greatly amplified when they are used in combination. Just as the practical usefulness of all-trans-retinoic acid in combination with conventional treatments continues to evolve, the use of differentiation agents in combination represents a novel and promising approach for oncologic therapy in the next decade. Although acute promyelocytic leukemia remains an "orphan" disease, its importance as a model for human neoplasia should not be minimized. The specific molecular lesion of acute promyelocytic leukemia is not shared by other cancers, but the physiologic actions of retinoids, their documented cytodifferentiating activity against a variety of human cancer cells in vitro, and their usefulness in cancer chemoprevention are clearly not mediated by identifiable mutations of retinoid receptors. The insights into transformation and leukemogenesis gained in acute promyelocytic leukemia may be a harbinger of further clinical applications and offer a glimpse into the next generation of cancer therapy.