Secondary metabolites produced by microorganisms have been important weapons used by man in fight against disease. Generally, the original microorganism isolated from nature produces low levels of the compound of interest and a substantial effort has to be expended on increasing the yields. One of the approaches used to achieve this is genetic manipulation of the culture, also called strain improvement. Often not much is known about the producer organism, the pathway for the biosynthesis of the compound of interest and its regulation. Therefore, an empirical or classical approach is used, which involves treating the culture with a physical or a chemical mutagen and screening the survivors for improved producers. This is a laborious process and to make the procedure more efficient, a number of selection methods, such as resistance to toxic analogues, have been designed. The development of molecular biological techniques has led to the new approaches such as "metabolic engineering". As the name suggests, the rate-limiting step in the biosynthesis is modified i.e. engineered, to increase the yield. As compared to the classical method, application of this technique requires substantial understanding of the biosynthetic pathway. At present both the empirical and the newer molecular biological methods are used for strain improvement.