Drug-resistant tuberculosis is emerging as a major global health challenge, fuelled by a limited formulary and reduced ability to timeously diagnose resistance. Furthermore, poorly managed drug-resistant tuberculosis is complicated by poor treatment outcomes and high rates of morbidity and mortality. A rapid diagnosis together with individualized management are essential in order to limit disease and curtail transmission. Recently, the feasibility of Whole Genome Sequencing (WGS) technology for the routine diagnosis and drug susceptibility testing of Mycobacterium Tuberculosis in a high income, low tuberculosis burden setting, was demonstrated. However, the use of WGS in low income settings, with the highest burden of disease, has not been evaluated. This viewpoint highlights the challenges and implications associated with the use of Whole Genome Sequencing for the diagnosis and management of drug-resistant tuberculosis in such settings.