Buruli ulcer is a noncontagious disabling cutaneous and subcutaneous mycobacteriosis reported by 33 countries in Africa, Asia, Oceania, and South America. The causative agent, , derives from by genomic reduction and acquisition of a plasmid-borne, nonribosomal cytotoxin mycolactone, the major virulence factor. -specific sequences have been readily detected in aquatic environments in food chains involving small mammals. Skin contamination combined with any type of puncture, including insect bites, is the most plausible route of transmission, and skin temperature of<30°C significantly correlates with the topography of lesions. After 30 years of emergence and increasing prevalence between 1970 and 2010, mainly in Africa, factors related to ongoing decreasing prevalence in the same countries remain unexplained. Rapid diagnosis, including laboratory confirmation at the point of care, is mandatory in order to reduce delays in effective treatment. Parenteral and potentially toxic streptomycin-rifampin is to be replaced by oral clarithromycin or fluoroquinolone combined with rifampin. In the absence of proven effective primary prevention, avoiding skin contamination by means of clothing can be implemented in areas of endemicity. Buruli ulcer is a prototype of ecosystem pathology, illustrating the impact of human activities on the environment as a source for emerging tropical infectious diseases.