The intrinsic ability of protein structures to exhibit the geometric and sequence properties required for ligand binding without evolutionary selection is shown by the coincidence of the properties of pockets in native, single domain proteins with those in computationally generated, compact homopolypeptide, artificial, ART structures. The library of native pockets is covered by a remarkably small number of representative pockets (~400), with virtually every native pocket having a statistically significant match in the ART library, suggesting that the library is complete.Finally, examples of experimental validation of promising small molecule hits that exploits the degeneracy of ligand binding pockets are presented.