Protein-based biologics, which leverage the inherent affinity and specificity of protein–protein interactions, offer an effective strategy for targeting and modulating disease pathways. Monoclonal antibodies have been the major focus of such drug discovery efforts, and while they have shown great clinical value, the breadth and complexity of human disease highlight the need for alternatives. The elucidation of molecular mechanisms underlying human disease has provided new opportunities for protein-based drugs to address challenging clinical problems. Natural ligands and receptors, which inherently modulate complex biological processes, have emerged as promising candidates for development of protein-based drugs with improved safety and efficacy.  As an example, rational and combinatorial methods will be described that were used to engineer a novel protein receptor that binds with femtomolar affinity to a clinical target of interest. Ultra-high binding affinity correlated with therapeutic efficacy and was critical for the ability of this engineered protein to inhibit tumor metastasis in several aggressive disease models. High-resolution structural studies provide an intriguing molecular rationale for increased binding affinity in this system, including reorientation of side chains throughout the binding interface and a receptor-induced conformational change that stabilizes co-complex formation.