The development of small-molecule drugs to counter the threat of bioterrorism will differ from classical drug discovery because it will be impossible to evaluate efficacy in clinical trials for many agents. This difference focuses biodefense on the identification of multiple drug candidates for each threat organism so that multiple treatments can be mounted simultaneously when needed to maximize the probability of success. Accordingly, drug discovery will become the rate- and cost-limiting phase of the overall drug development process. We address the potential of computational chemistry to optimize efficiency and efficacy in the discovery phase. The major elements required for a successful computational approach are the calculation of binding free energy, accounting for changes in solvation on ligand binding, and compensating for protein flexibility.