Management of Mycobacterium avium complex (MAC) lung disease is complicated, frequently unsuccessful and frustrating to patients and clinicians. The initial treatment effort may not be solely directed at MAC infection, rather it is often initiating airway clearance measures for bronchiectasis. The next important steps are deciding who to treat and when to initiate therapy. Definitive or unambiguous guidance for these decisions is often elusive. The evidence supporting the current macrolide-based regimen for treating MAC lung disease is compelling. This regimen has been recommended in consensus nontuberculous mycobacterial (NTM) treatment guidelines from 1997, 2007 and 2020, although clinician compliance with these recommendations is inconsistent. Understanding the idiosyncrasies of MAC antibiotic resistance is crucial for optimal antibiotic management. As a corollary, the importance of avoiding development of macrolide resistance due to inadequate therapy cannot be overstated. An inhaled liposome amikacin preparation is now approved for treating refractory MAC lung disease and holds promise for an even broader role in MAC therapy. Surgery is also an important therapeutic adjunct for selected patients. Microbiologic recurrences due either to new infection or treatment relapse/failure are common and require the same level of rigorous assessment and clinical judgement for determining their significance as initial MAC isolates. In summary, management of MAC lung disease patients is rarely straight forward and requires familiarity with multiple factors directly and indirectly related to MAC lung disease. The many nuances of MAC lung disease therapy defy simple treatment algorithms but with patience, attention to detail and perseverance, the outcome for most patients is favorable.