Multidrug-resistant and extensively drug-resistant Mycobacterium tuberculosis are no news and have contributed to the continued scourge of tuberculosis today. Acquisition of drug resistance by M. tuberculosis occurs due to mutations in genes, overexpression of some genes, and changes in the expression of specific genes. Thus, the development of resistance to first and second-line drugs. A fitness cost is also paid by drug-resistant M. tuberculosis. This is due to their weakened virulence, transmission, and reduced growth rate under normal growth conditions. Some studies show that “Persisters” or “Phenotypic drug-tolerant” populations occur in recovered patients. This results in a relapse of treated patients in immunosuppressive conditions. Findings suggest that drug-tolerant persister populations exist following antibiotic treatment, even if they are temporarily undetected by conventional microbiologic approaches. Drug resistance is a global issue that poses a danger to effective M. tuberculosis control. Even though drug resistance in M. tuberculosis is linked to changes in various genes, many resistant strains lack these common mutations. This review aims at delivering a comprehensive overview to global health authorities and prospective readers worldwide, thus improving the knowledge of the molecular basis of drug resistance in M. tuberculosis.