Mycobacterium ulcerans infection (Buruli ulcer) is a dramatically emerging disease reported from developing tropical and subtropical countries, and causes severe and lasting morbidity primarily in children. The epidemiology associates communities using rivers and slow flowing or stagnant water bodies (wetlands), often created as a result of human environmental disturbance. Natural reservoirs or modes of transmission are not known and it is sometimes called the Mysterious Disease; however, it was recently demonstrated that M. ulcerans could survive and multiply in biting aquatic bugs (Naucoridae), and they were able to transmit M. ulcerans to mice by their bites. The organism has been found in water, biofilm of aquatic plants, detritus, and invertebrates. A “Trophic Transmission Hypothesis” is discussed as a possible scenario for the natural mode of transmission of M. ulcerans. Additional studies on the ecological interactions of this bacterium are necessary for a more comprehensive epidemiological understanding of this mysterious disease.