Venom derived mini-proteins (e.g. knottins) have potential as therapeutic agents to modulate ion channels involved in cancer, autoimmunity and pain but can suffer from manufacturing difficulties, short half-lives and a lack of specificity. We have developed a novel molecular format wherein a peripheral CDR loop of an antibody has been replaced by a knottin. In this format (termed KnotBody), the antibody gains additional diversity within a scaffold pre-disposed to the blockade of ion channels, and the knottin enjoys the extended half-life, engineerability and manufacturability conferred by the antibody format. This presentation illustrates the generation of KnotBody inhibitors of multiple ion channels and their optimisation using phage and mammalian display.