Mycobacteria infections, such as tuberculosis and leprosy, cause devastation throughout the world, and even though decades of research have been focused on these diseases, the mechanisms of mycobacteria pathogenicity in general, and especially of Mycobacterium tuberculosis, are still not fully understood. The very long antibiotic treatment (between 3 and 6 months or even longer) necessary to cure mycobacteria infections has increasingly led to the appearance of strains resistant to multiple antibiotics. This trend makes the need to understand the course of mycobacterial diseases even more pressing. However, the complexity, difficult accessibility and ethical concerns linked to the use of mammalian models, such as non-human primates and mice, have hampered advancement in understanding the underlying molecular mechanisms. Mycobacterium marinum belongs to the genus of mycobacteria and is an established model to study mycobacteria pathogenicity in alternative host organisms [1–7]. In this chapter we focus especially on these “model” features of M. marinumand the experimental advantages it brings with it, especially in synergism with genetically tractable host organisms, both at systemic and cellular levels.Formore exhaustive overviews on infections caused by M. marinum, including its immunology and histopathological aspects, we would refer the reader to recent reviews [1, 3, 8].