Peptides exhibit some of the features of ideal drugs, most notably high bioactivity and exquisite specificity. However, their therapeutic development is generally complicated by poor bioavailability and pharmacokinetics, although these limitations can be substantially ameliorated through the inclusion on non-canonical structural features such as macrocyclisation and backbone N-methylation. Display methodologies (phage display, mRNA display, etc) are well established techniques for the isolation of peptides with high affinities to a target of interest. However, the peptides identified through such approaches are limited to canonical residues, restricting their therapeutic application. Genetic code reprogramming techniques circumvent these limitations, allowing the application of display screening to libraries of non-canonical peptides, and thereby allowing identification of truly drug-like peptidic molecules.1 The discovery of several such molecules (with structures ranging from mostly canonical peptides to molecules comprised almost entirely of non-canonical residues) will be described. These molecules exhibit nanomolar binding affinities and (often) inhibitory constants with respect to their cognate protein targets and can inhibit protein-protein interactions. In some cases these molecules were isolated from libraries engineered to exclude charged and/or polar residues (which are deleterious to pharmacokinetic characteristics such as stability in serum and oral availability), demonstrating that electrostatic interactions are not required for high affinity interactions between such molecules and their targets.