Polyketide natural products play an important role in the treatment of a wide range of human physiological disorders and in animal health and agriculture. The production of polyketides in heterologous hosts offers many advantages over the use of natural producers. Heterologous production systems can facilitate analysis of the catalytic properties of polyketide producing enzymes. These systems can also have an impact on the ability to make polyketide compounds from organisms that are difficult or impossible to culture. A number of factors must be considered in choosing a heterologous host. The host must be able to express relatively large polyketide proteins (300 kDa or larger), post-translationally modify these proteins, and produce adequate supplies of intracellular building blocks such as malonyl-CoA and methylmalonyl-CoA. For example, Streptomyces coelicolor has been used extensively to produce a variety of polyketides. Recent progress in increasing intracellular supplies of polyketide building blocks combined with the development of stable high copy number vectors has led to substantial increases in S. coelicolor polyketide titers. Escherichia coli has also emerged as an alternative expression host. This bacterium was extensively engineered to create a suitable host for polyketide production. E. coli has been used to produce a variety of polyketide compounds including 6-deoxyerythronolide B, yersiniabactin, and epothilone. With continued improvements to these and other systems, heterologous hosts promise to become a robust platform for large-scale polyketide production. (C) 2004 Elsevier Ltd. All rights reserved.