A study reports that the high prevalence of multidrug-resistant (MDR) tuberculosis (TB) and extensively drug-resistant (XDR) TB in Samara, Russia, is caused not only by deficiencies in the TB control programme but also by an unusual combination of resistance and compensatory mutations that enables Mycobacterium tuberculosis strains to retain clinical resistance without losing fitness or transmissibility. Whole-genome sequencing of 1,000 patient isolates revealed that 48% of all isolates were MDR and 16% of these were XDR; however, compensatory mutations that ameliorate the fitness costs of resistance were widespread. For example, compensatory mutations in over 400 rifampicin-resistant isolates were identified, including a newly discovered intragenic mutation in rpoB (encoding RNA polymerase β subunit). Furthermore, 65% of MDR isolates carried eis promoter mutations that cause kanamycin resistance, suggesting that extensive use of kanamycin might select for MDR-TB and enhance transmission.