Protein–protein interactions (PPIs) play a critical role in many essential biological processes, and numerous diseases result from malfunctioning PPIs. The modulation of undesirable PPIs via synthetic chemical molecules has long been considered of medical importance, but still remains challenging. Thanks to the development of synthetic chemistry, chemists can synthesize protein/peptide secondary structure mimics to modulate the specific PPIs. This review discusses general aspects of novel artificial peptide secondary structure mimics for the modulation of PPIs, their therapeutic applications and future prospects.