The International Union Against Tuberculosis and Lung Disease/World Health Organization Global Project on Anti-Tuberculosis Drug Resistance Surveillance recently released the fourth global survey, which documents the highest burden of multidrug-resistant tuberculosis (TB) yet reported. The best estimate of the number of new cases of multidrug-resistant disease occurring in 2006 is close to half a million and the recent recognition of extensively drug-resistant TB underscores the need for expanded surveillance, especially in areas in which TB control programs have been compromised by an escalating burden of TB and HIV. We review current methods used for drug resistance surveillance and describe methodologic obstacles for estimating the true extent of the problem, particularly in settings where HIV/TB coinfection is common or where a substantial portion of TB cases are treated in the private sector. We highlight practical challenges to the validity of surveillance studies and discuss how additional investment in laboratory capacity, diagnostic technologies, and sentinel site surveillance can improve our ability to estimate of the burden of drug-resistant TB.