Lasso peptides are an expanding class of compact bioactive ribosomally synthesized and posttranslationally modified peptide natural products (RiPPs) characterized by an interlocked lasso fold. These cyclic entangled structures (Figure ) can range from 13-33 residues in length and result from an isopeptide bond between the N-terminal amine and a side chain carboxylate, which forms a 7-9 residue macrolactam ring that is threaded by the C-terminal peptide tail. Once folded and cyclized, lasso peptides are extremely stable with their threaded tails held below the ring by steric locks, called plugs, formed by bulky side chains. In biological systems, lasso peptide maturation begins with the lasso precursor leader sequence to a RiPP precursor recognition element (RRE) that guides its cleavage by a leader peptidase, which enables a lasso cyclase to fold the lasso motif and catalyze the isopeptide bond formation. Once formed, the value of lasso peptides in nature is demonstrated by their diverse biological activities, including enzyme inhibition, receptor antagonism, and antibiotic effects, which are likely facilitated by their thermal stability, resistance to degradation, and rigid globular shapes. Accordingly, the lasso scaffold could be invaluable in the design of novel therapeutics that are sized between small molecules and biologics, which can lead to reduced immunogenicity and the capacity for bioavailibility. Collectively, lasso peptides warrant further investigation.