The pharmaceutical industry faces unprecedented pressures based largely on the inability to bring sufficient new medicines to market. The high failure rate of drug candidates in clinical development highlights a need for new approaches to the study of disease mechanisms and drug discovery. We advocate an integrated approach based on the study of the entire organism leveraging the power of detailed phenotyping, high-throughput genomic technologies and mathematical modeling. Key to this paradigm is the realization that the systematic genetic perturbations that exist in populations provide an ideal structure for uncovering the interactions that define molecular networks or states. By linking molecular states to physiological states and in turn understanding how molecular states drive disease processes, the promise of truly rational drug-design with a high probability of success in clinical development can be realized.