The human pathogen Mycobacterium tuberculosis has made a dramatic resurgence in recent years. Drug resistant and multidrug resistant strains are prevalent, and novel antibiotic strategies are desperately needed to counter Mtb's global spread. The M. tuberculosis genome sequence revealed an unexpectedly high number of cytochrome P450 (P450) enzymes (20), and parallel studies indicated that P450-inhibiting azole drugs had potent anti-mycobacterial activity. This article reviews current knowledge of structure/function of P450s and redox partner systems in M. tuberculosis. Recent research has highlighted potential drug target Mtb P450s and provided evidence for roles of selected P450 isoforms in host lipid and sterol/steroid transformations. Structural analysis of key Mtb P450s has provided fundamental information on the nature of the heme binding site, P450 interactions with azole drugs, the biochemical nature of cytochrome P420, and novel mutational adaptations by which azole binding to P450s may be diminished to facilitate azole resistance.