The occurrence of resistance to drugs used to treat tuberculosis (TB), and particularly multi-drug resistant TB (MDR-TB) defined as resistance to at least rifampicin and isoniazid, has become a significant public health dilemma in a number of countries and an obstacle to effective global TB control. HIV-associated MDR-TB understanding is vital in providing strategies for treatment of HIV and drug-resistant TB. Better understanding on the basis of drug action and resistance is a key to development of diagnostic strategies, novel drugs, and treatment programs, and to find an approach to study the pathogenicity of drug resistant strains. The effectiveness of strategies such as DOTS-Plus in the management of MDR-TB patients under program conditions should be tested in operational field clinical trials following strictly standardized definitions and nomenclature.