Mycobacterium tuberculosis the causative agent of tuberculosis has many intrinsic features which enable it to evade the activity of antibiotics. Many studies have been carried out to understand the mechanisms of drug resistance by this organism. An attempt was made in this write up to elucidate the various mechanism of drug resistance in M. tuberculosis, including its innate impermeable cell wall and mutation of specific genes. Drug resistance in Mycobacterium tuberculosis is not a product of a single homogeneous genetic unit. Rather it is as a result of frequent mutation in various genes which encode for resistance to antibiotics. Also, the slow metabolism during a prolonged dormant stage greatly enhances it resistance to drug, the waxy impermeable cell wall with the presence of numerous efflux pump are essential for withstanding the potency of antibiotics.Having an adequate knowledge on the molecular mechanisms of drug resistance in M. tuberculosis may be helpful in exploring new targets for drug development.