This article was based on a presentation given at the 26th International Pediatric Association Conference of Pediatrics, Johannesburg, South Africa, 4-9 August 2010. In 2009, there were 9.4 million new cases of tuberculosis (TB) globally, and, of these, approximately 1 million were pediatric cases. Drug-resistant TB makes up a relatively small proportion of new TB cases, but is much more likely in previously treated cases. Pediatric TB remains difficult to diagnose microbiologically, with the result that detection of drug-resistant TB in children is an ongoing challenge. Since children diagnosed with TB predominantly represent recently acquired TB infection, they provide an important indication of drug-resistant TB prevalence and transmission within their communities. Drug-resistant TB is essentially a man-made problem, which consumes large amounts of healthcare resources. Recent technologic advances may pave the way to more rapid and accurate diagnosis of TB in children. Similarly, these advances are likely to result in improved detection of drug-resistant pediatric TB isolates. The treatment of pediatric drug-resistant TB requires prolonged courses of expensive and potentially toxic drugs, many of which are not available in child-friendly formulations. New anti-TB drugs are at various stages of pre-clinical development and will hopefully allow for shorter, more effective treatment regimens in the not too distant future. HIV-infected children are at extremely high risk for TB acquisition and subsequent progression to symptomatic disease; therefore, many cases of pediatric drug-resistant TB occur in HIV-infected children. This often results in complicated pharmacologic regimens (including anti-TB and antiretroviral drugs) that are difficult to comply with and may have unpredictable interactions. There are limited reports of long-term clinical outcomes of children diagnosed with drug-resistant TB, but improvements in the diagnosis and pharmacologic management of these cases have the potential to improve the quality of care offered to these children.