Drug-resistant tuberculosis is a growing threat to global public health. Recent efforts to understand the evolution of drug resistance have shown that changes in drug-target interactions are only the first step in a longer adaptive process. The emergence of transmissible drug-resistant Mycobacterium tuberculosis is the result of a multitude of additional genetic mutations, many of which interact, a phenomenon known as epistasis. The varied effects of these epistatic interactions include compensating for the reduction of the biological cost associated with the development of drug resistance, increasing the level of resistance, and possibly accommodating broader changes in the physiology of resistant bacteria. Knowledge of these processes and our ability to detect them as they happen informs the development of diagnostic tools and better control strategies. In particular, the use of whole genome sequencing combined with surveillance efforts in the field could provide a powerful instrument to prevent future epidemics of drug-resistant tuberculosis.