Buruli ulcer is the third most frequent mycobacterial disease in humans, next to tuberculosis and leprosy, often causing serious skin ulcerations, bone deformities, and disability. Unlike TB and leprosy, Buruli ulcer has emerged dramatically since the 1980’s, with increasing numbers of cases being reported from at least 31 countries, mostly in tropical and subtropical areas, including Africa. Although poorly understood, the epidemiology of Buruli ulcer associates the resurgence with people who live and/or work close to wetlands, especially slow flowing (riverine) or stagnant water bodies (marshes, swamps), often created as a result of some human environmental disturbance. The disease is not known to be contagious between humans, and epidemiological studies have not yet established natural reservoirs or modes of transmission. However, it was recently demonstrated experimentally that M. ulcerans could survive and multiply exclusively within salivary glands of aquatic bugs (Naucoridae: Naucoris sp.) and they were able to transmit M. ulcerans to mice by their bites, suggesting a possible mechanism for human infection. The organism has been found in samples of water, biofilm and detritus. A possible trophic scenario for the natural mode of transmission of M. ulcerans is presented based on preliminary work in Ghana by the authors.