The discovery of antituberculosis drugs was the outcome of concerted efforts made between 1930 and 1970 to identify antimicrobial drugs. Streptomycin (1943) and rifampicin (1967), the first and the last of the great antituberculosis drugs currently in use, were discovered by screening of the products of soil bacteria. While streptomycin is a natural product, rifampicin is a semisynthetic drug resulting from extensive structural manipulations designed to render rifamycin SV more bioavailable. On the other hand, isoniazid and pyrazinamide are both derivatives of nicotinamide whose antituberculosis activity was quite accidentally discovered in 1945. Para-aminosalicylic acid or PAS is also a synthetic drug but was synthesized, not to improve an existing compound but as a hypothetical antagonist of salicylates which were known to increase respiration, and thus the growth of Mycobacterium tuberculosis. Like isoniazid, pyrazinamide and PAS, ethambutol is a product of organic synthesis. Perhaps the most striking feature of the history of antituberculosis drug discovery is the rational way the drugs have been tested and the drug combinations assessed as soon as the drugs became available.