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The Beijing genotype of Mycobacterium tuberculosis (MTB) is one of the most successful MTB lineages that has disseminated in the world. In China, the rate of multidrug-resistant (MDR) tuberculosis is significantly higher than the global average rate, and the Beijing genotype strains take the largest share of MDR strains. To study the genetic basis of the epidemiological findings that Beijing genotype has often been associated with tuberculosis outbreaks and drug resistance, we determined the genome sequences of four clinical isolates: two extensively drug resistant (XDR1219, XDR1221) and two multidrug resistant (WX1, WX3), using whole-genome sequencing. A large number of individual and shared SNPs of the four Beijing strains were identified. Our isolates harbored almost all classic drug resistance-associated mutations. The mutations responsible for drug resistance in the two XDR strains were consistent with the clinical quantitative drug resistance levels. COG analysis revealed that Beijing strains have significantly higher abundances of the mutations responsible for cell wall/membrane/envelope biogenesis (COG M), secondary metabolites biosynthesis, transport and catabolism (COG Q), lipid transport and metabolism (COG I) and defense mechanisms (COG V). The shared mutated genes of the four studied Beijing strains were significantly overrepresented in three DNA repair pathways. Our analyses promote the understanding of the genome polymorphism of the Beijing family strains and provide the molecular genetic basis for their wide dissemination capacity and drug resistance.