Aided by genome-mining strategies, knowledge of the prevalence and diversity of ribosomally synthesized natural products (RNPs) is rapidly increasing. Among these are the lantipeptides, posttranslationally modified peptides containing characteristic thioether cross-links imperative for bioactivity and stability. Though this family was once thought to be a limited class of antimicrobial compounds produced by gram-positive bacteria, new insights have revealed a much larger diversity of activity, structure, biosynthetic machinery, and producing organisms than previously appreciated. Detailed investigation of the enzymes responsible for installing the posttranslational modifications has resulted in improved in vivo and in vitro engineering systems focusing on enhancement of the therapeutic potential of these compounds. Although dozens of new lantipeptides have been isolated in recent years, bioinformatic analyses indicate that many hundreds more await discovery owing to the widespread frequency of lantipeptide biosynthetic machinery in bacterial genomes.