Fish mycobacteriosis is a chronic bacterial disease that has the potential for infecting most fish species from both freshwater and saltwater habitats. The causative agents of fish mycobacteriosis are three species of Mycobacterium: M. chelonae, M. fortuitum, and M. marinum. Infections of fish by these bacteria result in a slow, degenerative disease with symptoms that include wasting, fading of color, exophthalmia, and frequently, granulomas and other types of skin ulcers. The disease is transmissible from fish to fish and also from fish to man, where the bacteria produce a potentially serious medical condition. Little is known about the molecular biological aspects of the disease or the host-pathogen interactions. Using the knowledge gained from recent advances in the study of M. tuberculosis and other human mycobacterial pathogens, we suggest a set of strategies to begin a molecular biological study of fish mycobacteriosis. Although no conclusions may be drawn at this early stage in understanding this disease, the prospects are very good that the techniques of molecular biology will shed light on this longstanding and misunderstood disease.