Mycobacterium tuberculosis has demonstrated remarkable ability to survive in diverse conditions encountered during the infection process. These involve surviving the bactericidal stresses within the macrophage, the anaerobic and nutritionally altered environment of the granuloma, and the metabolically inactive latent state. Understanding the molecular basis of this adaptive behavior lies in the identification of genes (or virulence determinants) specifically expressed under these varied conditions. Transcriptional control plays a key role in regulating gene expression in response to environmental signals. However, even after decades of investigation our knowledge about the function of these regulatory mechanisms in mycobacteria remains meagre. But the elucidation of the genome sequence and implementation of sophisticated molecular genetic approaches to this organism have made a revolutionary impact on the study of mycobacterial pathogenesis. Deletion and complementation of individual genes can be done at will facilitating the comparative analysis of mutants and wild-type strains. Novel and powerful technologies such as DNA microarrays, fluorescent beacons and proteomics have made possible the analysis of the expression levels of multiple genes in in vitro systems. More technically challenging uses of these techniques is being undertaken to explore pathogen gene expression within the host. This will lead to the identification of virulence factors and give definitive insight into their regulatory signals.