**Abstract**

Tuberculosis (TB) is one of the deadly diseases in the present era caused by *Mycobacterium tuberculosis*. Principally, this bacterium attacks the lungs, however, MTB Has been observed affecting any part of the human body including the kidney, spine, and brain. Drug-resistant progression and other associated properties of MTB become a major hurdle in drug discovery to fight against tuberculosis. Moreover, some of the challenging situations such as the low range of chemical agents, the time-consuming process of drug development, the shortage of predictive animal models, and inadequate information of the physicochemical evidence required for effective bacterial penetration, are additional hindrances for the pharmaceutical scientist. In the current chapter, we focus on challenges encountered during drug discovery and need to be overcome as *M. tuberculosis* has a substantial barrier in its lipid-containing cell wall to inhibit the influx of drugs which is the initial requirement of the drug to show its therapeutic effect. There is also an immediate need for efficient vaccine development which may show its effect on adolescents and adults along with infants. Investigation on key bacterial targets has been troublesome, in light of the vulnerability around the microenvironments found in vivo and subsequently, the importance of exceptional metabolic pathways. The manuscript is prepared after the extensive literature survey to explore the vigorous approaches in novel drug designing and in proposing potent drug targets. The re-engineering and repositioning of prominent antitubercular drugs are required to attain viable control.

**Keywords:** *Mycobacterium tuberculosis*, drug, challenges, bacterial targets
