In enzymes, multiple organic residues of moderate reactivity work together to facilitate heterolytic bond formation and cleavage under mild conditions. For example, class I aldolases use a combination of weakly acidic and basic residues to catalyze the aldol condensation (Fig. ). Conserved lysine and aspartate residues work cooperatively to generate the key enamine intermediate, all within a tightly hydrogen-bonded network that facilitates proton transfer and circumvents high-energy charged species. These lessons from biology have gained renewed relevance in the context of biomass utilization. Active sites in which the reactivity of the whole is greater than the sum of the individual parts provide significant stability and selectivity advantages. Weakly reactive functional groups are more resistant to poisoning by contaminants and less prone to unselective substrate polymerization and fouling, two of the most common catalyst degradation pathways observed in biomass conversion technologies. Inspired by class I aldolases and other enzymes, bifunctional acid-base catalysts have been explored in multiple platforms, including small molecule amino acid and peptide catalysts (Fig. ), functionalized organic polymers of both synthetic and biological origin (Fig. ), and amine-grafted silica (Fig. ). Clear cooperative effects have been observed in reactions relevant to biomass conversion, including the aldol condensation of biomass-derived methyl ketones into higher molecular weight biofuel precursors, and the condensation of biomassderived aldehydes (e.g., furfural, 5-hydroxymethylfurfural) into higher value products. Fully realizing the promise of enzyme-like cooperativity in a synthetic platform requires the ability to adjust active site parameters by as little as a few angstroms. In enzymes, the relative spatial rearrangement of amino acid residues is as critical to function as their number and identity. For example, lengthening the aspartate residue in a class I aldolase active site by just a single methylene unit dramatically reduces catalytic activity by over 40-fold. This level of spatial precision is difficult, if not impossible, to replicate in supports such as amine-grafted mesoporous silica, where structural fidelity is fundamentally limited by the amorphous surface.