Prevention of drug resistance became the most important aim following the first clinical trial on streptomycin with a randomized intake in 1948. The occurrence of resistance was reduced by combined therapy with streptomycin and p-aminosalicylic acid and prevented by an initial phase with three drugs. Following the Madras comparison of domiciliary and sanatorium therapy, chemotherapy for the whole world became available, but there remained the problem of compliance during 1 year of treatment. Solutions were sought by the use of intermittently supervised drug administration, and in 1970, by the inclusion of the two major sterilizing drugs rifampicin and pyrazinamide, in regimens lasting only 6 months. The next 15 years were devoted to defining modern regimens, the first with a four-drug initial phase and rifampicin throughout (2EHRZ/4RH), and the second with a continuation phase of ethambutol and isoniazid (2EHRZ/6EH). Considering individual drugs, rifampicin and pyrazinamide provide almost all of the bactericidal activity, whereas isoniazid is bactericidal only during the first 2 days and thereafter prevents the emergence of drug resistance. Although models in vitro and in the mouse suggest that drug efficacy is related to area under the concentration-time curve/minimal inhibitory concentration (AUC/MIC), clinical trials with intermittent regimens indicate that this relationship is not present during human therapy.