Natural products derived from the secondary metabolism of microbes constitute a cornerstone of modern medicine. Engineering bugs to produce these products in high quantities is a major challenge for biotechnology, which has usually been tackled by either one of two strategies: iterative random mutagenesis or rational design. Recently, we analyzed the transcriptome of a Streptomyces clavuligerus strain optimized for production of the β-lactamase inhibitor clavulanic acid by multiple rounds of mutagenesis and selection, and discovered that the observed changes matched surprisingly well with simple changes that have been introduced into these strains by rational engineering. Here, we discuss how in the new field of synthetic biology, random mutagenesis and rational engineering can be implemented complementarily in ways which may enable one to go beyond the status quo that has now been reached by each method independently.