Multidrug-resistant (MDR) tuberculosis (TB) denotes bacillary resistance to at least isoniazid and rifampicin. Extensively drug-resistant (XDR) TB is MDR-TB with additional bacillary resistance to any fluoroquinolone and at least one second-line injectable drugs. Rooted in inadequate TB treatment and compounded by a vicious circle of diagnostic delay and improper treatment, MDR-TB/XDR-TB has become a global epidemic that is fuelled by poverty, human immunodeficiency virus (HIV) and neglect of airborne infection control. The majority of MDR-TB cases in some settings with high prevalence of MDR-TB are due to transmission of drug-resistant bacillary strains to previously untreated patients. Global efforts in controlling MDR-TB/XDR-TB can no longer focus solely on high-risk patients. It is difficult and costly to treat MDR-TB/XDR-TB. Without timely implementation of preventive and management strategies, difficult MDR-TB/XDR-TB can cripple global TB control efforts. Preventive strategies include prompt diagnosis with adequate TB treatment using the directly observed therapy, short-course (DOTS) strategy and drug-resistance programmes, airborne infection control, preventive treatment of TB/HIV, and optimal use of antiretroviral therapy. Management strategies for established cases of difficult MDR-TB/XDR-TB rely on harnessing existing drugs (notably newer generation fluoroquinolones, high-dose isoniazid, linezolid and pyrazinamide with in vitro activity) in the best combinations and dosing schedules, together with adjunctive surgery in carefully selected cases. Immunotherapy may also have a role in the future. New diagnostics, drugs and vaccines are required to meet the challenge, but science alone is insufficient. Difficult MDR-TB/XDR-TB cannot be tackled without achieving high cure rates with quality DOTS and beyond, and concurrently addressing poverty and HIV.