Specifically, the production of chemicals at high titers, yields and rates involves optimizing the cellular resources typically devoted to biomass formation with precursors and cofactors for product formation. This is not straightforward because genetic changes intended for a certain effect have been found to cause unanticipated strain behavior, partially due to the inbuilt redundancy of metabolic networks. This presentation will show examples where the use of computational modeling and system based omics approaches has helped decipher strain performance, assisted in the design of experiments to diagnose strain performance bottlenecks, and guided rational strain engineering to address the bottlenecks. In addition to transcriptome, metabolome, proteome and flux analysis data, often employed in an integrated fashion, the use of next generation sequencing has proven critical to elucidating strain performance.