Small cyclic peptides are appealing scaffolds for drug discovery, and have the capacity to inhibit protein-protein interactions, making them applicable to targeting the ~85% of the human proteome that is considered “undruggable”. However, the pharmacokinetic characteristics of such peptides are generally poor, with oral availability, systemic clearance and the ability to cross cell membranes (and thereby access intracellular targets) all problematic. Natural product cyclic peptides circumvent these limitations through the incorporation of non-canonical moieties (e.g. backbone amide N-methylation, or sidechains involving O- or N-methylation) that reduce hydrogen bonding potential leading to improved bio-availability and stability. We have investigated the compatibility of a range of non-canonical hydrophobic amino acids (including alkyl, aromatic, N- and/or O-methylated moieties) with ribosomal synthesis. This has allowed the synthesis of extremely diverse (>1012) libraries of peptide-like molecules containing such residues through the use of genetic code reprogramming techniques. Moreover, because these peptides are synthesised ribosomally, they can be rapidly screened for affinity to a therapeutic target of interest by mRNA display, yielding highly active protein-protein interaction inhibitors with “drug-like” structural characteristics. Specific examples will be presented.