Recent genetic studies demonstrate that mice deficient in the forkhead box m1b (Foxm1b) transcription factor are highly resistant to developing hepatocellular carcinoma, which is among the most lethal cancers worldwide. In addition, the Foxm1b transcription factor was identified as a novel inhibitory target of the p19^ARF tumor suppressor during early stages of liver tumorigenesis, but p19^ARF expression is extinguished in hepatic tumors that develop at later stages. Structure–function studies demonstrate that amino acids 26–46 of the p19^ARF protein are sufficient to bind Foxm1b and reduce Foxm1b transcriptional activity by targeting it to the nucleolus. A peptide containing amino acids 24–46 of p19^ARF, which was modified to enhance cellular uptake, is an effective inhibitor of Foxm1b transcriptional activity and prevents Foxm1b stimulation of anchorage-independent growth of cells on soft agar. Thus, the p19^ARF peptide is an effective inhibitor of Foxm1b and represents a potential therapy for hepatocellular carcinoma.