We have entered a new era of peptide drugs, with 8 of the top 12 drugs by dollar sales being injectable peptides. Peptides are also attracting public notoriety as unsanctioned sports 'medicines'. However, the takeup of peptides for wider applications is still limited by high costs, conformational flexibility, metabolic instability, poor membrane permeability, low oral bioavailability and immunogenicity. To overcome these problems, proteins are being downsized to small peptides of <20 residues corresponding to bioactive protein surfaces, but they do not normally adopt stable structures in water. Cyclization can compress and organize peptides into water-stable bioactive structures, protect against degrading enzymes, and enable cell permeation, but can it confer oral bioavailability? Here we highlight some cell permeable and orally bioavailable cyclic peptides, showing chemical and structural effects of cyclization, heterocyclic constraints, unnatural amino acids, and hydrogen bond shielding. NMR and CD spectra can guide flexibility/rigidity, hydrogen bond strength, and component shielding from solvent to increase cell uptake. Chemical changes can improve oral bioavailability, alter mechanisms of cell uptake, reduce plasma clearance and tissue partitioning. Finally, we show that increasing residence time of cyclic peptides on receptors can compensate for low oral bioavailability. This challenges the convention that membrane permeability, plasma concentration and oral bioavailability necessarily predict oral efficacy, and that blood levels of drugs must correlate with patient responses.