Peptides are thought of as poor drugs because of their poor cell permeability and poor oral bioavailability. However, recent studies have challenged this notion, showing that cyclic peptides can have small molecule-like oral bioavailability.1,2 To understand the rules that might govern the oral bioavailability of cyclic peptides, we have explored the relationship between their structures and their permeability. In our initial work, we investigated the importance of the hydrogen bonding network, and found that NMR amide temperature coefficients can be used to identify exposed amides that can be modified by N-methylation. Using this knowledge, we designed a peptide with high in vitro permeability and an oral bioavailability of 33% in a rat model.3 We extended this work by measuring the hydrogen bonding potential and lipophicility of 62 cyclic hexapeptides using experimental (i.e. NMR and chromatography) and computational (i.e. molecular dynamics) methods, as well as their permeability in PAMPA and Caco-2 assays.4 By correlating the measured structural parameters of the cyclic peptides to their permeability, we found an interesting interplay between peptide permeability, lipophilicity and hydrogen bonding potential. We observed that peptides with very high permeability have high lipophilicity and few solvent hydrogen bond interactions, whereas peptides with very low permeability have low lipophilicity or many solvent interactions. Our findings have broad implications to the development of peptides into drugs.