The increasing rate of drug resistance in tuberculosis possesses a great challenge to the global tuberculosis control. The drug resistance in Mycobacterium tuberculosis (M. tuberculosis) is mainly conferred by chromosomal mutations in essential and highly conserved genes, and usually accompanied by a reduction in fitness, namely “fitness cost”. However, this fitness cost can be ameliorated by secondary compensatory mutations which help restore the fitness of drug-resistant strains. The compensatory evolution has been regarded as the biological basis of the extensive spread and high prevalence of drug-resistant M. tuberculosis. Recently, a series of scientific works in the field of molecular epidemiology of tuberculosis and the basic research on the compensatory evolution of drug-resistant M. tuberculosis have been conducted. In this review, we focus on the molecular mechanisms for fitness cost of drug resistance, the compensatory evolution and the potential impacts of these two processes on the transmission of M. tuberculosis.