The p53-hDM2 protein interaction is a validated therapeutic target in cancer. We report the synthesis of stabilized alpha-helix of p53 (SAH-p53) compounds that antagonize the p53-hDM2 interaction. We demonstrate that hydrocarbon stapling confers cellular permeability to a p53 peptide that is then capable of modulating transcriptional activity. The lead SAH-p53 compound triggers apoptosis in hDM2-overexpressing cancer cells by reactivating the native p53 signaling pathway. SAH-p53 is the first example of an all-hydrocarbon i, i+7 stabilized peptide that subverts cancer through direct modulation of a transcriptional pathway.