Isoniazid (INH) is the only anti-tuberculous drug for which a relationship has been noticed between acquisition of resistance and lack of virulence. Mutation in katG gene is the chief cause for INH resistance in Mycobacterium tuberculosis (MTB). Classical studies have demonstrated that INH-resistant (INH^r) mutants with a defective katG gene were catalase deficient and markedly attenuated in guinea pigs. Also, earlier studies on south Indian INH^r isolates were shown to have lower virulence and higher susceptibility to H₂O₂. However, later studies including that of our's suggest that INH resistance is not always accompanied by compromised virulence and/or survival. Therefore, this review focuses on the influence of INH resistance on virulence of MTB from global and south Indian isolates.