Recent worldwide emergence of multidrug-resistant and extensively drug-resistant tuberculosis is threatening to destabilize tuberculosis control programs and urging global attention to the development of alternative tuberculosis therapies. Major roadblocks limiting the development and effectiveness of new drugs to combat tuberculosis are the profound innate resistance of Mycobacterium tuberculosis to host defense mechanisms as well as its intrinsic tolerance to chemotherapeutic reagents. The triangle of interactions among the pathogen, the host responses, and the drugs used to cure the disease are critical for the outcome of tuberculosis. We must better understand this three-way interaction in order to develop drugs that are able to kill the bacillus in the most effective way and minimize the emergence of drug resistance. Here we review our recent understanding of the molecular basis underlying intrinsic antibiotic resistance and survival tactics of M. tuberculosis. This knowledge may help to reveal current targets for the development of novel antituberculosis drugs.