We report here the development of a pathogenesis model utilizing Mycobacterium marinum infection of zebrafish (Danio rerio) for the study of mycobacterial disease. The zebrafish model mimics certain aspects of human tuberculosis, such as the formation of granuloma-like lesions and the ability to establish either an acute or a chronic infection based upon inoculum. This model allows the genetics of mycobacterial disease to be studied in both pathogen and host.