Resistance in Mycobacterium tuberculosis arises from man-made selection of genetic mutants that result from spontaneous chromosomal alterations. Thus, drug-resistant tuberculosis (TB) is generally due to inappropriate treatment regimen, poor drug quality, erratic drug supply and poor patient adherence to treatment, reflecting failure in the implementation of an effective TB control programme. Multidrug-resistant TB (MDR-TB) usually denotes bacillary resistance to at least isoniazid and rifampicin. Proper implementation of the directly observed treatment, short-course (DOTS) strategy should achieve a high cure rate for disease and curtail the development of drug resistance. Innovations in reinforcement of this strategy should further facilitate its delivery and enhance its effectiveness. However, established MDR-TB is notoriously difficult to treat, and necessitates the use of alternative specific antituberculosis chemotherapy regimens. These regimens comprise combination use of second-line antituberculosis drugs, that are generally more costly and toxic, and have to be given for longer durations. The fluoroquinolones, better tolerated by patients, have a pivotal role in MDR-TB treatment. Optimal delivery of these treatment regimens mandates a programmatic basis which is now included under the Stop-TB Drug-Resistance Programme(s). The key components embrace political commitment, quality-assured drug susceptibility testing, reliable supply of quality drugs, delivery of chemotherapy under directly observed settings, and a sound recording and reporting system to monitor the individual treatment outcome of patient and overall performance of the TB control programme. Adjunctive surgery in selected MDR-TB patients help to improve their treatment success. Further exploration is required regarding the use of immunotherapy. The recent emergence of extensively drug-resistant TB (XDR-TB), representing MDR-TB with additional bacillary resistance to fluoroquinlones and one or more of the second-line injectable drugs -kanamycin, amikacin and capreomycin, threatens the global control of TB. Given the escalating size of the problem of MDR-TB and XDR-TB worldwide, gigantic instillation of resources is required for control of this formidable challenge, largely through more accurate and rapid drug susceptibility testing (especially for rifampicin and fluoroquinolone), regular drug-resistance surveillance, development of new antituberculosis drugs and other therapeutic modalities, intensive infection control, especially in HIV care settings, as well as strengthening of currently functioning DOTS and Drug-Resistance Programmes.