Leprosy is caused by Mycobacterium leprae. Currently, leprosy control is mainly based on WHO-recommended multi-drug treatment; thus, emergence of drug resistance is a major concern. M. leprae isolates resistant to single and multiple drugs have been encountered. In this review, the history of chemotherapy and drug resistance in leprosy and molecular biological insights for drug resistance are described. New methodologies to test susceptibility to anti-leprosy drugs instead of the traditional mouse footpad method are introduced. Awareness of the need to monitor drug resistance to prevent the spread of resistant cases is emphasized.