Mycobacterial skin and soft tissue infection (SSTI) includes nontuberculous mycobacterial (NTM) infections, tuberculosis (TB), and leprosy. Diagnosis of mycobacterial SSTI can be challenging due to diverse clinical presentation, low yield from cultured specimens, and nonspecific histopathology on tissue biopsy. In addition, immunosuppressed patients may present with atypical or disseminated disease. Despite aggressive medical treatment and often with surgical intervention, results may be suboptimal with poor outcomes. Regimens typically require multiple antibiotics for extended periods of time and are often complicated by medication side effects and drug-drug interactions. Biopsy with culture is the gold standard for diagnosis, but newer molecular diagnostics and proteomics such as matrix-assisted laser desorption ionization-time of flight mass spectrometry have improved diagnosis with increased identification of clinically significant mycobacteria species in clinically relevant time frames. We will review updates in diagnostic tests along with clinical presentation and treatment of mycobacterial SSTI for NTM, TB, and leprosy.