Tuberculosis (TB) remains as one of the leading causes of morbidity and mortality among infectious diseases worldwide. Although lipids (mainly fatty acids and cholesterol) have been reported to play an important role during active and latent infection of M. tuberculosis, there are other molecular aspects of bacterial response to those substrates that are not fully understood, involving gene regulation background. This review highlights recent insights on pathogen gene expression: regulation during its active growth, during survival in presence of lipids and under variable hostile host microenvironments. We also propose several application options of this knowledge that may contribute for improved TB control. •The role of lipids in the survival and adaptation of M. tuberculosis within different host microenvironments are detailed.•The role of transcriptional factors as modulators that drive lipid metabolism of bacilli for survival is critically valued.•The importance of investigating ncRNAs, and genes related to lipid metabolism during the TB infection is examined.•Some approaches for TB control based on genetic response of M. tuberculosis to a lipid-rich environment are discussed.