A number of promising new classes of compounds are currently in pipeline at various stages of discovery and clinical development. An ideal therapy should consist of drugs that are active against the drug resistant varieties of M.tb they as well as can effectively target the sleeping bacilli lying within tubercular lesions. Phenothiazines are known to have anti-mycobacterial activity for more than four decades. As the first line drugs against TB were able to effectively contain the AMN107 company disease, phenothiazines were not given much importance early on. Now with the advent of MDR strains of M.tb, compounds that can either be used directly or as adjuncts with the current drugs or may serve as lead compounds for the synthesis of new anti-TB drugs, are gaining importance. Trifluoperazine is a calmodulin antagonist in eukaryotes and has been used as an antipsychotic drug in neuroleptic patients. Phenothiazines have been reported to affect the calciumdependent ATPases, thereby reducing the amount of cellular energy required to maintain the active transport processes. In mycobacteria, TFP has been shown to negatively affect processes like protein and lipid synthesis. We have previously characterized the mycobacterial gene Rv1211 as coding for a Calmodulin-like-Protein in M.tb, with the ability to complex with calcium. Our studies showed that this CAMLP-Ca2+ complex could stimulate heterologous targets like plant NAD Kinase and bovine brain phosphodiesterase. Knowing that TFP is a eukaryotic Calmodulin antagonist, we have checked its effect on M.tb CAMLP activities and have found it to be inhibitory. In the present work, we demonstrate the efficacy of TFP in suppressing the growth/survival of two clinical isolates of MDR M.tb in vitro as well as ex vivo. TFP also exerted lethal effect against stress induced persistent M.tb, thereby showing the potential to be effective against dormant TB. The resistance of M.tuberculosis to various stresses has been considered one of the major factors that have led to its success as an intracellular pathogen. This is so because M.tuberculosis is located in pulmonary cavities within caseous material where the pH, oxygen and nutrition are sufficiently low. Not only this, the active immune response of host to this pathogen involves release of highly reactive oxygen and nitrogen intermediates, which are toxic to the bacilli. But mycobacterium has developed various strategies to counteract these conditions. Antibiotics used to treat TB infection are usually active against growing bacteria but not against the dormant pathogen. Correlation between antibiotic activity and bacterial growth state in streptomycin-dependent M.tb was shown almost 30 years ago. The antibiotic-resistance of nongrowing bacteria is due to changes in bacterial metabolism or physiological state and is described as phenotypic resistance. While the dormant bacilli are known to effectively escape the immune system acquiring phenotypic resistance to the current first line drugs, many clinical isolates have been found to have developed genetic level resistance to TB chemotherapy. Hence the need of the hour is development of drugs that can prevent the pathogen from surviving in a drug-resistant state. Such drugs in combination with the current antibiotics can reduce the period of treatment for complete cure and lead to global eradication of TB. Though many reports have indicated the anti-mycobacterial activity of TFP, but its exact mechanism of action is not yet clearly understood.