Functional genomics and proteomics are identifying many potential drug targets for novel therapeutic proteins, and both rational and combinatorial protein engineering methods are available for creating drug candidates. A central challenge is the definition of the most appropriate design criteria, which will benefit critically from computational kinetic models that incorporate integration from the molecular level to the whole systems level. Interpretation of these processes will require mathematical models that are refined in combination with relevant data derived from quantitative assays, to correctly set biophysical objectives for protein design.