Recent advances in the 'omics' technologies, scientific computing and mathematical modeling of biological processes have started to fundamentally impact the way we approach drug discovery. Recent years have witnessed the development of genome-scale functional screens, large collections of reagents, protein microarrays, databases and algorithms for data and text mining. Taken together, they enable the unprecedented descriptions of complex biological systems, which are testable by mathematical modeling and simulation. While the methods and tools are advancing, it is their iterative and combinatorial application that defines the systems biology approach.