Tuberculosis still remains an important health problem. Understanding the mechanisms of drug resistance in Mycobacterium tuberculosis is important in the control of the disease. Although drug resistance in M. tuberculosis is mainly due to spontaneous chromosomal mutations in genes encoding drug target or drug activating enzymes, the resistance cannot be explained only by these mutations. Low permeability of the cell wall, efflux pumps and drug inactivating enzymes are other mechanisms of drug resistance in mycobacteria. In this review efflux pumps, as new mechanisms of drug resistance and probable targets of novel drugs, in M. tuberculosis, were discussed.