Mycobacterium tuberculosis (MTB) has been an exceptionally successful human pathogen over the centuries, infecting almost one-third of the global population. An exponential increase in tuberculosis (TB) cases, mainly by the drug-resistant (DR) strains of MTB, has created an urgent need for identifying and developing new antituberculosis drugs acting via novel mechanisms. The multi drug-resistant (MDR) TB and extensively drug-resistant (XDR) TB strains, accelerating through drug specific resistance amplification, are resistant to a majority of antibiotics used in the treatment and are challenging to remove from the host’s system. Since proteins are the functional beings of the biological arrangement, they make promising drug targets for immunodiagnostics or therapeutics. To identify and characterize such novel proteins, which directly or indirectly regulatedrug resistance in mycobacteria, proteomics approaches could be successfully employed. Serological techniques like immunoassay have higher chances of rendering false positive or false negative results and hence could be rectified by using more sophisticated techniques like mass spectrometry. In the past two to three decades, proteomics-based approach has seen a pivotal rise. The application of proteomics-based approaches has helped to gain insights into MTB and its relevance to clinical science. They have aided in the identification and characterization of novel proteins. To have a better understanding of pathophysiology of MTB, proteome-based science could help simultaneously in the identification of proteins, which can be potential targets. Recent progress in the area of proteomics has opened up the doors to address many previously unanswered questions, with studies on DR-TB being no exception. The Beijing family of MTB forms an interesting candidate for proteomic analysis as it constitutes 13% of the global isolates and has higher chances of acquiring drug resistance. Proteomics can play an important role in the discovery of biomarkers for TB and other diseases. Also, it can aid in the development of effective vaccines as well as simple, rapid, and cost-effective tests for the diagnosis of TB, which are crucial for the management and control of the disease.