Bioengineers have mastered practical techniques for tuning a biomaterial’s properties with only limited information on the relationship between the material’s structure and function. These techniques have been quintessential to engineering proteins, which are most often riddled with ill-defined structure–function relationships. In this Perspective, we review bioengineering approaches aimed at overcoming the elusive protein structure–function relation. We extend these principles to engineering synthetic nanomaterials, specifically applying the underlying theory to optical sensors based on single-stranded DNA-wrapped single-walled carbon nanotubes (ssDNA-SWCNTs). Bioengineering techniques such as directed evolution, computational design, and noncanonical synthesis are reviewed in the broader context of nanomaterials engineering. We further provide an order-of-magnitude analysis of empirical approaches that rely on random or guided searches for designing new nanomaterials. The underlying concepts presented in these approaches can be further extended to a broad range of engineering fields confronted with empirical design strategies, including catalysis, metal–organic frameworks (MOFs), pharmaceutical dosing, and optimization algorithms.