Interest in peptide drug discovery is surging. In the past several years,numerous pharmaceutical and biotech companies have committed considerable resources to peptide-based drug discovery. In part,this is being fueled by an increasing recognition that peptide drugs combine many of the virtues of small molecules and proteins, while minimizing several of their drawbacks, and that peptides can potentially expand the druggable space to include intracellular, extracellular and membrane associated protein–protein interactions. Moreover, powerful new in vitro and in silico technologies and breakthroughs in our understanding of natural peptides have emerged that provide peptide chemists with the toolsand insights they need to solve the various pharmacokinetic problems that often plague peptide drug discovery efforts. From stapled peptides,to highly versatile macrocyclic peptides and disulfide-rich peptides, to other peptides with various nonstandard chemistries, peptides are poised to fulfill their promise of providing a drug class that straddles the chemical space between small molecules and proteins, ultimately resulting in transformational medicines and improved clinical outcomes.