This chapter discusses the regulatory role of the phosphorylation of the tumor suppressor protein, Par-4 (PAWR, PRKC, apoptosis Wilm’s tumor 1 (WT1)), which is highly expressed in various tissues. One of the most appealing characteristics of Par-4 is its ability to selectively induce apoptosis in cancer cells but not in normal or immortalized cells. This feature can mainly be explained by the fact that Par-4 is regulated by various posttranslational modifications and primarily by phosphorylation. Indeed, Par-4 contains multiple phosphorylation sites, located in different domains of the protein, which modulate its pro-apoptotic functions, localization, cleavage by caspases, as well as its dimerization with partners of biological consequence. Notably, in mammals Par-4 phosphorylation is tightly regulated by kinases in a species-specific manner that either favors (PKA) or inhibits its pro-apoptotic activity (AKT and CK2). A complex interplay exists between Par-4, its cleaved form, and the kinase, AKT1, whose mechanisms entail an additional level of regulation, involving the casein kinase 2 (CK2). The phosphorylation of Par-4, which is induced by different kinases in a coordinated way and underlie Par-4 multifaceted impacts, suggests that Par-4 could be an “Achilles heel” of cancer cells that could be exploited in the framework of anticancer research.