The diverse physiological and pathophysiological roles of peptide–protein and protein–protein interactions provide potential opportunities for therapeutic intervention in a wide range of diseases. In retrospect, peptide drug discovery has faced substantial challenges in achieving its full potential towards modulating such biological processes, due to inherent limitations in overcoming susceptibility to proteolytic degradation, cell penetration and achieving suitable in vivo pharmacokinetic profiles. Unsurprisingly, in part owing to such challenges, peptide drug discovery has historically been restricted to extracellular and receptor target space (e.g., G-protein coupled receptor agonists or antagonists). This Chapter highlights a renaissance of peptide drug discovery relative to drug design, chemical space, cell permeability and drug delivery to tackle an expanding target space that is no longer restricted to only extracellular and receptor targets. Noteworthy are past milestones in peptide science and technology, including the first and second waves of marketed peptide drugs, as well as the current focus on exploiting the peptide modality to tackle “undruggable” target space (relative to small molecules or antibodies) such as intracellular protein–protein interactions. Unquestionably, a worldwide network of academic and biotech/pharma drug hunters has grown significantly to date and is driving the third wave of peptide drug discovery. For those of us who have been deeply engaged in the quest for peptide breakthrough medicines and disruptive innovation over many years there may be a sense of “there and back again”; however, there is a new mounting enthusiasm to re-engage the peptide modality for providing hope to many who suffer with life-threatening and debilitating disease.