Until 2004, the skin disease known as Buruli ulcer, caused by Mycobacterium ulcerans, could only be treated by surgery and skin grafting. Although this worked reasonably well on early lesions typically found in patients in Australia, the strategy was usually impractical on large lesions resulting from diagnostic delay in patients in rural West Africa. Based on promising preclinical studies, treatment trials in West Africa have shown that a combination of rifampin and streptomycin administered daily for 8 weeks can kill M. ulcerans bacilli, arrest the disease, and promote healing without relapse or reduce the extent of surgical excision. Improved treatment options are the focus of research that has increased tremendously since the WHO began its Global Buruli Ulcer Initiative in 1998.