###### Abstract  
After several years of limited success, an effective regimen for the treatment of both drug-sensitive and multiple-drug-resistant tuberculosis is in place. However, this success is still incomplete, as we need several more novel combinations to treat extensively drug-resistant tuberculosis, as well newer emerging resistance. Additionally, the goal of a shortened therapy continues to evade us. A systematic analysis of the tuberculosis drug discovery approaches employed over the last two decades shows that the lead identification path has been largely influenced by the improved understanding of the biology of the pathogen _Mycobacterium tuberculosis_. Interestingly, the drug discovery efforts can be grouped into a few defined approaches that predominated over a period of time. This review delineates the key drivers during each of these periods. While doing so, the author's experiences at AstraZeneca R&D, Bangalore, India, on the discovery of new antim mycobacterial candidate drugs are used to exemplify the concept. Finally, the review also discusses the value of validated targets, promiscuous targets, the current anti-TB pipeline, the gaps in it, and the possible way forward.  
tuberculosis; _Mycobacterium tuberculosis_; drug discovery; drug development; target-based screening; phenotypic screening; antituberculosis agents; antim mycobacterial; anti-TB drug pipeline; privileged targets; promiscuous targets; lead generation  
Chemotherapy for the treatment of tuberculosis has evolved over a period of several decades, starting from the 1950s. The discovery of drugs with superior effectiveness that are part of the current regimen has been facilitated through the success of several novel approaches and technologies. While the medical need has at times hastened newer approaches to be adopted, the main driver for the improvement has been the increased understanding of the biology of the pathogen, as well as its interaction with the human host. In this review, we try to discuss the discovery of new drugs in groups, with the groups sharing a common key driver that precipitated the changes of the treatment regimen. As 'newer aspects of the biology' of the pathogen became known, they provided opportunities to build novel drug discovery approaches. The paper also uses as examples the approaches, the results, and the learning gathered as a part of the antituberculosis (anti-TB) program at Astra Zeneca, R and D, Bangalore, India (AZI).  
Several of the drugs that have been discovered are based on the learning that followed the introduction of each of the new compounds into the drug regimen. The data have several pointers; while each of the successful drugs was discovered building on the then state of the knowledge, the newer drugs themselves also helped in the further understanding of the pathogen biology. This is even reflected in the current set of drugs that are in late-stage development or have been recently introduced into the anti-TB regimen.  
The anti-TB drugs currently in use, and those in the late stages of clinical development, can be broadly pooled into the following groups:  
1. Serendipitous drug discovery--early chemotherapy;
2. Modification of drug scaffolds;
3. Revisiting targets that have clinically validated drugs against them (referred to as established targets);
4. Target-based screening;
5. Phenotypic screening.