Cellular complexity makes it difficult to build a complete understanding of cellular function but also offers innumerable possibilities for modifying the cellular machinery to achieve a specific purpose. The exploitation of cellular complexity for strain improvement has been a challenging goal for applied biological research because it requires the coordinated understanding of multiple cellular processes. It is therefore pursued most efficiently in the framework of systems biology. Progress in strain improvement will depend not only on advances in technologies for high-throughput measurements but, more importantly, on the development of theoretical methods that increase the information content of these measurements and, as such, facilitate the elucidation of mechanisms and the identification of genetic targets for modification.