Leprosy is a chronic disease caused by Mycobacterium leprae infection. Multidrug therapy, which consists of dapsone, rifampicin, clofazimine, and quinolone, is the currently accepted strategy for leprosy control. However, drug-resistant cases of M. leprae have been reported sporadically in some countries or areas soon after the initiation of dapsone chemotherapy. Susceptibility or resistance to antileprosy drugs has been determined using the mouse footpad method since the 1960s. Obtaining comprehensive data on the prevalence or dissemination of resistant strains has been hampered due to the methodological faults of the method. However, recent findings on relationships between resistance to dapsone, rifampicin, and quinolones and genetic background have enabled the detection of resistance to these key drugs by analyzing amino acid substitution in a drug resistance determining region. Resistance to drugs used in multidrug therapy is a concern of the WHO Global Leprosy Programme. Global surveillance of drug resistance was instituted in 2008 to assess the level of drug resistance and evaluate the efficacy of the current leprosy control strategy. The surveillance network consists of sentinel sites in 18 countries for sample collection and 18 reference centers for mutation detection by PCR direct sequencing. To date, results indicate that drug-resistant M. leprae does not threaten the current globally accepted procedures for the control of leprosy.