Skp2 is an oncoprotein that mediates the degradation of several negative regulators of the cell cycle to promote cell proliferation. A recent report by Huang and colleagues reveals that Skp2 directs the ubiquitylation and subsequent degradation of FoxO1, a member of the FoxO family of transcription factors. Since FoxO proteins possess tumor suppressor functions, this new finding suggests a new mechanism by which Skp2 may favor tumorigenesis.