Collectively, the examples discussed here reveal distinct strategies discovered by nature to optimize the free energy of functionally important states. Although it is easier to explicitly represent and discuss specific and enthalpically directed interactions like hydrogen bonds, improved ensemble representations of macromolecular structure should allow for us to integrate structural and entropic information for perspective design of function. After all, nature cares about free energy, regardless of whether the source is easy to describe. Even if the energetic impact of conformational entropy is relatively small in some cases, the move from ensemble-averaged singular representations of protein structure to ensemble views could parallel the revolution catalyzed by single cell methods in genomics. In single cell work, the diversity of cell types and behaviors masked by bulk methods is leading to new insights into the properties of systems . Indeed, the configurational entropy of cell types may also play a role in tissue organization, connecting the importance of considering statistical mechanical concepts in decoding function across scales . In the case of macromolecules, we look forward to future work that highlights how rare states contribute to specific functions and how conformational entropy can be leveraged as part of the toolkit to solve challenges in design, catalysis, and cellular signaling.