Crystal and NMR structures have provided novel insights into BH3-only induced Bax and Bak activation and oligomerization [Czabotar et al. 2013, Moldoveanu et al. 2013, Brouwer et al. 2014]. In particular, this work has revealed the nature of the activation sites, an ensuing separation of the Bax and Bak core and latch domains and subsequent dimerization of the released cores. Here we present the first crystal structure of Bak in complex with an activating BH3 domain. This reveals insights into differences in interactions of BH3‑only proteins with Bak compared to pro-survival relatives and provides possible mechanisms towards the unlatching of the Bak globular fold. Based on the structure we have made a novel modification that changes the activity of the BH3 peptide dramatically. No longer does it bind transiently to the target and induce conformational change, instead it binds with measurable affinity to Bak and inhibits conformational change. As a consequence this peptide acts as a Bak inhibitor in permeabilization experiments, to our knowledge this is the first example of an agent that can directly bind to and inhibit Bak. These findings provide novel insights into Bak activation and new strategies for developing therapeutics capable of inhibiting Bak activity.