Certain BH3-only proteins transiently bind and activate Bak and Bax, initiating conformational changes that lead to oligomerisation and result in permeabilisation of the mitochondrial outer membrane, a pivotal step in the mitochondrial pathway to apoptosis [1, 2]. Here we describe the first crystal structures of an activator BH3 peptide bound to Bak . These revealed a central cavity which may promote critical conformational changes upon activator BH3 binding. Peptides possessing non-natural amino acids were designed that fill this cavity and promote stability of the complex. These peptides stabilised Bak and inhibited its membrane permeabilisation activity . These are the first structure based inhibitors of Bak or Bax and provide a molecular rationale for developing inhibitors of cell death for conditions in which excessive apoptosis is implicated such as ischemic reperfusion injury, hearing loss and acute stress related injuries.