Venomous and hematophagous animals use toxins from their venom or salivary glands to assist in obtaining food. Honed through millions of years of evolutions, these toxins are efficient and efficacious molecules that could potentially be developed into therapeutic agents. Drugs such as captopril, eptifibatide, lepirudin, ziconotide are some successful examples. We have previously isolated a potent and specific thrombin-inhibiting peptide, variegin, from the salivary gland extracts of the tropical bont tick, Amblyomma variegatum. Variegin has partial similarity with bivalirudin, an FDA-approved direct thrombin inhibiting peptide designed by human. However, variegin inhibits thrombin with a Ki value of 0.3 nM, which is >9X more potent than bivalirudin at 2.9 nM. We have subsequently designed and developed a large collection of thrombin-inhibiting peptides guided by prior knowledge, crystal structures, bioinformatics and extensive structure-function relationships studies. Interestingly, we have found that ticks similarly developed a collection of related and redundant peptides in their saliva, building their own ‘focused chemical library’ against the target (thrombin) in their hosts (mammals), mirroring drug design efforts through evolution. Leveraging on the libraries ‘built’ by the ticks and ourselves, we have developed extremely potent peptides with Ki values as low as 4 pM for thrombin, which is >600X better than bivalirudin. We have tested variegin in murine and porcine models of thrombosis and bleeding, established its promising potential as a peri-procedural anticoagulant in percutaneous coronary intervention.