The increase in multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant in vitro to at least isoniazid (INH) and rifampicin (RIF), is a global concern. It is estimated that 511 000 MDR-TB cases occur globally each year. The World Health Organization (WHO) consequently released an emergency update on their management guidelines, recommending that treatment of MDR-TB should include at least 4 effective drugs, and that standardised treatment regimens should be based on resistance patterns for each country/region. Most importantly, treatment regimens should not depend on the results of drug susceptibility testing (DST) for ethambutol (EMB) or pyrazinamide (PZA). In response, the South African Department of Health prepared a draft drug-resistant TB treatment policy in which PZA remains one of the 4 effective drugs, while EMB should be replaced with terizidone or cycloserine, if there is resistance to EMB (disregarding inaccurate DST). In South Africa, there is a high frequency of undetected EMB and PZA resistance and their association with MDR-TB. Therefore, we recommend that the WHO guidelines in which 4 other effective drugs are used to treat MDR-TB, be followed more closely. EMB and PZA can be included if they are not counted as one of the 4 effective drugs. However, this does not address the root cause of the amplification of resistance in undiagnosed MDR-TB patients in South Africa, which can only be achieved by the implementation of rapid DST methods in all TB cases before initiating therapy. This protocol would curb the amplification of resistance and the evolution of XDR-TB. The number of MDR-TB cases has steadily increased despite the widespread implementation of the directly observed treatment short-course (DOTS) and DOTS-plus strategies. (1,2) A survey in South Africa estimates that 1.8% of new TB cases and 6.7% of retreatment TB cases are MDR-TB, (1) equating to approximately 14 000 MDR-TB cases each year. (1) The manner in which the WHO DOTS strategy has been implemented in South Africa to control TB might have inadvertently lead to the amplification of resistance in MDR-TB cases. (3-5) Consequently, it is important to review the epidemiology of drug resistance in the country and make informed evidence-based suggestions on improving the current treatment strategy.