Metabolic engineering has been defined as "the improvement of cellular activities by manipulation of enzymatic, transport, and regulatory functions of the cell with the use of recombinant DNA technology" [Bailey, J. E. (1991). Toward a science of metabolic engineering. Science, 252,1668-1675]. As such, it mimics the processes of natural evolution by engineering new traits through directed alterations in gene expression, mutation, disruption, or copy number. Therefore, studies of the mechanisms by which new traits evolve in nature hold important lessons that can be used to guide the design of novel metabolic engineering strategies. Likewise, lessons derived from laboratory-based metabolic engineering studies might enable the development of improved methods for better controlling the evolution of new traits in nature. In this article we will discuss these concepts within the context of an important and alarming example of natural evolutionary forces, antibiotic resistant bacteria. We will describe several examples of the major mechanisms by which antibiotic resistance has evolved in nature and relate these to previous, current, and possible future metabolic engineering efforts. (c) 2004 Elsevier Ltd. All rights reserved.