Here, we review evidence of how nature has evolved to harness protein conformational entropy. The first principle is most well known: pre-paying entropic costs through ordering in the initial, or ground, state. The second phenomenon is spatial entropic redistribution: increasing conformational entropy in one region of the protein or system in response to a decrease in conformational entropy elsewhere in the system. The third concept extends the concept of spatial redistribution to catalytically competent ensembles: conformational entropy in the enzymatic scaffold, distant from the catalytic site, contributes to lowering transition state barriers. Further explorations of these mechanisms could profoundly impact our understanding of binding events, catalysis, and cell signaling. After all, without explicitly considering conformational entropy, we ignore a large thermodynamic component driving free energy. Now is the time to apply a conformational entropy lens to our explanation of protein function and begin applying that lens prospectively to ligand and protein design.