By converting a disordered polymer into a globular structure, protein folding reduces many conformational degrees of freedom, resulting in a significant conformational entropy penalty. Nonetheless, residual entropy persists in the protein's native state as it fluctuates between thermally accessible conformations. Here, we review biophysical evidence, primarily from NMR studies, for how conformational entropy modulates the free energy of ligand binding and catalysis. The major theme that emerges is that selection based on free energy has converged on mechanisms to mitigate the effects of entropy loss during crucial functions like binding or catalysis. The modulation of conformational entropy occurs primarily via two main mechanisms: pre-paying entropic costs through ordering in the ground state and spatial compensation through increases in conformational entropy in distal regions after binding. In examining these mechanisms, it also becomes clear that conformational entropy is highly intertwined with classic definitions of conformational changes. We argue that given the ample evidence of the biological significance of conformational entropy, structurally defining the ensembles encoding conformational entropy will open new paths for control of binding, catalysis, and allostery.