Acting as the key step of various cell signaling pathways, protein-protein interaction (PPIs) plays a significant role in the regulation of biological functions. Many of the proteins involved are potential drug targets, therefore manipulation of PPI would greatly a great interest in physiology and pharmacology. Most PPIs could not be directly targeted by small molecule drugs due to their flat and shallow interaction surfaces. Selective regulator may be obtained by extraction and chemical synthesis helical peptide that forms folding substructure scaffold in PPI. However, most peptides when separated from its protein progenitor are not able to maintain its biological active helical structure, but tend to form random coil conformation, which is vulnerable to enzyme and suffer low potency and drugability. By modification through all-hydrocarbon bridged cyclic peptide designating ‘stapled peptide’, it turned out to be the most effective and directive methodology to solve the drawbacks. Stapled peptide not only can boost its potency, but also its biostability and cell permeability. These significant advantages make peptide stapling an important way of modification, which may definitely generate more and more peptide drug candidates targeting PPIs in the foreseen future. In this paper, chemistry and bioactivity of the stapled peptides reported up-to-date are systematically reviewed and discussed.