Certain synthetic retinoid-related molecules induce apoptosis in cancer cells through a novel mechanism of retinoid action that is independent of the nuclear retinoid receptors. These compounds target protein kinases and protein phosphatases to trigger signal transduction pathways that lead to apoptosis. Whereas retinoid agonists such as CD437 activate stress kinases via inhibition of the phosphatase MKP-1, the retinoid antagonist MX781 inhibits the survival kinase IKK. These retinoid-mediated signaling pathways converge at the mitochondria, where they cause the release of cytochrome c and subsequent Apaf-1-dependent activation of caspases. Identification of the retinoid targets that mediate their apoptotic activity will enhance our understanding of the mechanism of this novel retinoid action, to allow appropriate optimization of currently available compounds to advance into the clinic as novel anticancer agents.