Mathematical models predict that the future of the multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemic will depend to a large extent on the transmission efficiency or relative fitness of drug-resistant Mycobacterium tuberculosis compared to drug-susceptible strains. Molecular epidemiological studies comparing the spread of drug-resistant to that of drug-susceptible strains have yielded conflicting results: MDR strains can be up to 10 times more or 10 times less transmissible than pan-susceptible strains. Experimental work performed with model organisms has highlighted a level of complexity in the biology of bacterial drug resistance that is generally not considered during standard epidemiological studies of TB transmission. Recent experimental studies in M. tuberculosis indicate that drug resistance in this organism could be equally complex. For example, the relative fitness of drug-resistant strains of M. tuberculosis can be influenced by the specific drug resistance-conferring mutation and strain genetic background. Furthermore, compensatory evolution, which has been shown to mitigate the fitness defects associated with drug resistance in other bacteria, could be an important factor in the emergence and spread of drug-resistant M. tuberculosis. However, much more work is needed to understand the detailed molecular mechanisms and evolutionary forces that drive drug resistance in this pathogen. Such increased knowledge will allow for better epidemiological predictions and assist in the development of new tools and strategies to fight drug-resistant TB.