Overcoming complex therapeutic challenges requires next-gen precision and targeting for maximum efficacy. Conventional discovery approaches fall short since they are not guided by structure and are thereby limited in their ability to target specific epitopes. We introduce a novel approach: by leveraging high-throughput, high-resolution structure determination, we systematically engineer high-affinity antibodies that selectively bind a target epitope— ensuring exceptional precision and efficacy against even unstructured, multimeric or otherwise structurally challenging targets.