The incidence of Mycobacterium kansasii varies widely over time and by region, but this organism remains one of the most clinically relevant isolated species of nontuberculous mycobacteria. In contrast to other common nontuberculous mycobacteria, M. kansasii is infrequently isolated from natural water sources or soil. The major reservoir appears to be tap water. Infection is likely acquired through the aerosol route, with low infectivity in regions of endemicity. Human-to-human transmission is thought not to occur. Clinical syndromes and radiological findings of M. kansasii infection are mostly indistinguishable from that of Mycobacterium tuberculosis, thus requiring microbiological confirmation. Disseminated disease is uncommon in HIV-negative patients and usually associated with severe immunosuppression. The majority of patients with M. kansasii pulmonary disease have underlying pulmonary comorbidities, such as smoking, chronic obstructive pulmonary disease, bronchiectasis, and prior or concurrent M. tuberculosis infection. Surveys in Great Britain, however, noted higher rates, with 8 to 9% of M. kansasii infections presenting with extrapulmonary disease. Common sites of extrapulmonary disease include the lymph nodes, skin, and musculoskeletal and genitourinary systems. The specificity of gamma interferon release assays (IGRAs) for M. tuberculosis may be reduced by M. kansasii infection, as M. kansasii encodes CFP-10 and ESAT-6, two antigens targeted by IGRAs. A study conducted to evaluate the therapy in rifampin-resistant disease found that patients with acquired rifampin resistance were treated with daily high-dose ethambutol, isoniazid, sulfamethoxazole, and pyridoxine combined with aminoglycoside therapy. Given the potential toxicities, particularly with aminoglycoside therapy, clarithromycin and/or moxifloxacin therapy could be considered as alternatives.