Buruli disease, caused by Mycobacterium ulcerans, is an emerging infectious disease in tropical areas, particularly West Africa, which can cause deep necrotizing skin lesions, called Buruli ulcer. Buruli disease affects all age groups but about 50% of the cases are diagnosed in children. There is no evidence that Buruli disease is transmitted by direct person-to-person contact and it is very likely that contaminated water of rivers, swamps and lakes serves as the wildlife reservoir of M. ulcerans. This review briefly discusses the epidemiology, microbiology, pathology and treatment of the disease. It describes in detail the current knowledge of the immune response and focuses on the studies that have dealt with vaccination. Finally, experimental approaches for future immunoprophylaxis are discussed.