Aberrant protein-protein interactions have been cited in numerous diseases. However, it is difficult to target protein-protein interactions by small molecules as the dimensions of these protein-protein interfaces (≥600Å2) are larger than typical small molecules. We demonstrate the feasibility of utilizing a robust β-sheet scaffold for targeting thrombin as proof of principle. Thrombin is a trypsin-like serine protease generated in the penultimate step of the blood coagulation cascade. Many drugs target thrombin to prevent aberrant clot formation seen in venous and arterial thrombosis. We have been able to identify thermostable, structured β-sheet epitopes from a phage-display library that inhibit thrombin's proteolytic activity with Ki's in the low micromolar range. An interesting observation is the emergence of Tyr residues at the first and fifth randomized positions for all these inhibitory proteins, which lead to the construction of a minimal small molecule inhibitor of thrombin function. On going results in targeting the Vascular Endothelial Growth Factor (VEGF) and beta-amyloid proteins will also be presented.