The patterns of multiple-drug resistance of the nontuberculous mycobacteria as judged from population analysis of recent isolates are described. In this article the various possible mechanisms of drug resistance in these mycobacteria (high frequencies of spontaneous mutation, drug-resistance factors, permeability, and exclusion) are analysed in light of current evidence. Epidemiologic and bacteriologic arguments are presented that appear to refute the hypothesis that high frequency of spontaneous mutation and drugresistance factors explain multiple-drug resistance. Preliminary work suggesting that resistance in nontuberculous mycobacteria may be caused by the failure of antibiotics to reach the cytoplasmic membrane is discussed.