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International audience; From their observation of necrotic areas around bacterial foci in Buruli ulcers (BUs), Connor and co-workers were the first, back in 1965, to suggest that M. ulcerans may produce a diffusible cytotoxin [1]. This hypothesis was later confirmed by injecting mycobacterial culture filtrates into the skin of guinea pigs, showing that this causes focal necrosis resembling that of naturally occurring human infections [1–3]. In 1999, George et al. succeeded in isolating a cytotoxic factor from M. ulcerans lipid extracts, and deciphered its chemical nature [4]. The M. ulcerans toxin was named mycolactone, based on its mycobacterial origin and macrolactone structure: a 12-membered lactone ring, to which a C5-O-linked polyunsaturated acyl side chain and a C-linked upper side chain comprising C12–C20 are appended (Fig. 1). Follow-up studies showed that M. ulcerans-derived mycolactone was in reality a mixture of two stereoisomers called A and B [6, 7] (Fig. 1). Since the initial discovery of mycolactone A/B, eight additional mycolactone congeners have been identified that are either produced by M. ulcerans strains of different geographical origins or genetically related fish and frog pathogens, which were initially given different species designations such as M. pseudoshottsii and M. liflandii. Comparative genome analysis later revealed that all mycolactone-producing mycobacteria evolved from a common M. marinum-like progenitor, and are therefore ecovars of a single M. ulcerans species [8]. While the macrolide core structure and upper side chain are conserved, mycolactone populations from different M. ulcerans sub-lineages vary in the length, number and localization of hydroxyl groups and number of double bonds of the lower side chain. These modifications of the lower polyunsaturated acyl side chain cause pronounced changes in cytotoxicity [9–11]. The origin and chemistry of natural mycolactones, structure-activity relationships and the various approaches that were developed to generate synthetic mycolactones have been reviewed recently [12, 13]. These aspects will therefore not be further discussed here. Instead, this chapter provides an update on our understanding of mycolactone (A/B) biology, and discusses its proposed mechanisms of action in relation with BU pathogenesis.