The blocking of protein protein interactions ( PPI) is a challenging but exciting area of modern drug development. Two well-characterized systems involving important targets in oncology are currently under intense investigation the Bcl2 system and the p53 system. In both cases small molecule PPI drugs have entered human clinical trial. The discovery of small molecules that can potently inhibit such interactions has shown that they are indeed druggable and the small molecule inhibitors show exceptional specificity. Such molecules are hard to find and develop however so many attempts have been made to convert inhibitory peptides, which are easily discovered PPI blockers into effective drugs. One such method involves the attachment of transporter peptides while another uses an additional all hydrocarbon cross link to “staple” the peptide and make it active in cell based and animal assays. Using the mdm2 system we have developed and characterized stapled peptides that activate the p53 response, while others have developed BH3 mimetic peptides. The area is controversial, as attempts to repeat certain published observations in the BH3 mimetic field have failed. We are therefore engaged in an intense analysis of the Mdm2 inhibitors we have made to try and understand what controls the effectiveness of the stapled peptide approach. Our studies reveal how easy it is to make errors of interpretation in this system and that the presence of the staple and tight binding to the target are not sufficient to ensure efficacy. Instead effective cellular uptake is the critical design feature and much effort will be required to design peptides that combine all the properties required for an effective drug. Even with effective inhibitors of the p53 mdm2 interaction in hand the selection of the right tumors to treat and the possible side effects of such p53 activating compounds require intense study before the best use of such future medicines can be determined.