Skin and soft tissue infections are common presentations for non-tuberculous mycobacteria (NTM). The cutaneous infections caused by NTM may cause localized or diffuse lesions. M. ulcerans is one of the most identified pathogens that involves in the skin and soft tissue mycobacterial infections. Meanwhile, M. marinum, as an NTM has also become important emerging causal agents of cutaneous disease in various geographical regions. Although having common ancestry and highly similar in genetic makeup, M. ulcerans and M. marinum have differential impacts on the host innate immune system. In term pathogenesis, prolonged cell exposure to exotoxin mycolactone produced by M. ulcerans could lead to Buruli ulcer. Meanwhile, like most pathogenic mycobacteria, M. marinum evades the host immune responses by invading and replicating inside host cells and it is capable of modulating host immune responses. This article aims to provide a general overview and comparisons between the pathogenesis, diagnosis, prevention and therapeutic strategies for M. ulcerans and M. marinum.