The discovery and development of novel constrained peptides that combine the advantages of therapeutic proteins with those of small molecules has partially prompted the re-emergence of peptides as therapeutics. In this regard, lasso peptides are characterized by both the selectivity and potency of larger protein biologics but with no or low immunogenicity, and the stability and bioavailability of small molecules. Moreover, the diverse functionality of lasso peptides and their extraordinary stability against chemical, thermal and proteolytic degradation make them attractive candidates for drug discovery. However, the chemical synthesis of lasso peptides remains a challenge due to the difficulty in building and maintaining their threaded structure. From a therapeutic point of view, these small and constrained structures would provide a new paradigm in drug discovery.