The contradictory properties of RNA-binding proteins (RBPs) have mystified their roles in human diseases including cancer. Are certain RBPs oncogenes or tumor suppressors? In the case of the signal transduction activator of RNA metabolism (STAR) family of hnRNP K homology (KH)-domain-containing RBPs, the dominant view with loose experimental evidence is that these proteins are tumor suppressors. However, recent developments support a pro-oncogenic role for archetypical STAR protein Sam68. Sam68-null mice are not prone to cancer, but instead display pronounced defects in mammary gland ductal development, and haploinsufficiency of Sam68 impedes mammary tumor onset and tumor multiplicity in mouse models expressing the mammary-targeted polyoma middle T antigen oncogene. These advances have increased the interest in the role of Sam68 as a positive regulator of cancer progression and position Sam68 as a viable therapeutic target. Retrospective and perspective implications of Sam68 in cancer are discussed.