Tuberculosis (TB) remains an important global public health problem with an estimated prevalence of 14 million people with TB worldwide in 2007. Since antibiotic treatment is one of the main tools for TB control, knowledge of Mycobacterium tuberculosis drug resistance is an important component for the disease control strategy. Although several gene mutations in specific loci of the M. tuberculosis genome have been reported as the basis for drug resistance, additional resistance mechanisms are now believed to exist. Efflux is a ubiquitous mechanism responsible for intrinsic and acquired drug resistance in prokaryotic and eukaryotic cells. M. tuberculosis presents one of the largest numbers of putative drug efflux pumps compared to its genome size. Bioinformatics, as well as direct and indirect evidence have established relationships among drug efflux with intrinsic or acquired resistance in M. tuberculosis. This mini-review describes the current knowledge on drug efflux in M. tuberculosis.