The key to successful elimination of tuberculosis (TB) is treatment of cases with optimum chemotherapy. Poor chemotherapy over time has led to drug-resistant disease. Drug resistance of Mycobacterium tuberculosis develops by the selective growth of resistant mutants. The incidence of drug-resistant cases depends on the number of bacilli and the drug-resistant mutants in the lesion. The latter is low for individual drugs and even lower for two and three drugs. Therefore, use of combination chemotherapy with three or more drugs results in cure. However, irregular treatment, inadequate drugs, inadequate drug doses or addition of a single drug to a failing regimen allows selective growth of resistant mutants and acquired drug-resistant TB. Contacts of these resistant cases develop primary drug resistant TB. Thus, drug resistance in tuberculosis is a “man-made problem”. Anti-TB chemotherapy must be given optimally by (i) ensuring adequate absorption of drugs, (ii) timely diagnosis and management of drug toxicities and (iii) treatment adherence. New classes of anti-TB drugs are needed; but are unlikely to become available soon. It is vital that the 21st century physicians understand the basic principles of TB chemotherapy to ensure efficient use of available drugs to postpone or even reverse epidemics drug-resistant TB.