Disruption of protein:protein interactions can often be achieved with synthetic peptides which are capable of binding their targets with high affinity and specificity. As such, synthetic peptides have long been considered for clinical applications to antagonise or activate cell signaling pathways. In this presentation, our efforts to target the cell death or apoptosis pathways regulated by interactions between the pro-death and pro-survival members of the Bcl-2 family of proteins are reported. As this pathway is frequently dysregulated in cancer, new strategies to activate the pathway in a highly specific manner provide a potential avenue for therapeutic application of Bcl-2 antagonists. Accordingly, through rational design as well as screening of large peptide libraries, we have developed highly potent peptide-based ligands that can specifically target particular pro-survival Bcl-2 proteins 1 . We will present data on how viral delivery of such ligands can be used to effectively kill tumour cells lines (e.g. acute myeloid leukaemia cells) as well as primary tumour cells from patients 2 , providing proof-of-principle for similar-acting drugs. Moreover, modification of the peptide sequences through incorporation of non-natural amino acids, specifically beta-amino acids, renders them highly stable compared to their natural BH3 peptide counterparts, an important first step in their direct clinical application 3 . High resolution X-ray crystallographic structural data on how such peptides engage their targets will be presented 4, 5, 6 , together with how this information can be used to rationally design new sequences with altered binding profiles 6 . These data have wider application for the design of unnatural peptide ligands for other cellular targets.