Interest continues to increase in the use of folding modulators to overcome problems with heterologous protein folding in Escherichia coli. Currently, this approach, though highly successful with a number of individual proteins, remains a somewhat hit-and-miss affair. Ongoing research directed at unraveling the precise role and specificity of these folding modulators should generate a clearer understanding of the potential and limitations of overexpressing folding catalysts in vivo. This will facilitate the development, in the not too distant future, of a more structured and rational approach to improving the folding of heterologous gene products in E. coli.