Mycobacterium tuberculosis remains a leading infectious cause of morbidity and mortality. While antibiotic resistance is cited as a potential threat to efforts aimed at controlling the spread of this pathogen, it is not clear how drug resistance affects disease dynamics. The effect of mutational events that lead to antibiotic-resistant phenotypes may or may not have a predictable effect on the fitness of drug-resistant tuberculosis strains. Here, we review the literature on laboratory studies of the fitness of drug-resistant tuberculosis, we examine the evidence from cluster studies, and we consider the effect of drug resistance on disease dynamics in mathematical models. On the basis of these diverse lines of evidence, we conclude that the fitness estimates of drug-resistant M tuberculosis are quite heterogeneous and that this variation may preclude our ability to predict future trends of this pathogen.