Mycobacterium avium-intracellulare complex (MAC) infections are frequently encountered in immunocompromised hosts, especially AIDS patients, although nodular-bronchiectasis type MAC infections without predisposing conditions are steadily increasing, particularly in Japan. Clinical control of MAC infection is difficult, since it responds poorly to available antimycobacterial regimens because of the intrinsic resistance of MAC organisms to common antituberculosis drugs, although some antimycobacterial drugs, such as macrolides (clarithromycin, azithromycin), ethambutol, clofazimine and rifamycins (especially rifabutin), are fairly or modestly effective in controlling AIDS-associated MAC bacteremia. In addition, treatment of pulmonary MAC infections is also difficult, even with available antimycobacterial multi-drug therapies. The insufficient efficacy of the majority of ordinary antimycobacterial drugs in treating MAC diseases is principally due to the low susceptibility of MAC to the majority of ordinary antimycobacterial drugs, the extremely wide range of susceptibilities of MAC isolates to most antimicrobial drugs, and the fact that polyclonal MAC infections are occasionally seen in AIDS patients. Therefore, the development of new antimicrobials and administration protocols that are safe and potently effective against MAC infections is urgently needed. However, despite the gradual but steady increase in the incidence of MAC infections, and thereby the urgent call for new drug development, new drugs that are truly useful for the treatment of refractory MAC diseases continue to elude us. In this review article, the following topics will be described: (1) the present status of the existing anti-MAC drugs, with special reference to the recent findings of the in vitro and in vivo anti-MAC activities of macrolides and other moderately useful drugs, such as new rifamycins, clofazimine and some fluoroquinolones, and (2) the present status and future prospects of the development of new promising antimicrobials with anti-MAC activity.