The ability of molecules to adopt more than one unique crystalline structure, polymorphism, is a phenomenon of considerable scientific interest because it challenges the notion that molecules arrange themselves exclusively in the thermodynamically most stable crystal form. The factors influencing this behavior are manifold and have defied simple prediction. To illustrate an approach to elucidating these factors, the solid-state behavior of a series of molecules that are derivatives of tolfenamic acid (TA), a pentamorphic system, was explored. In analogy to the manner in which drugs are discovered through structure–activity relationships and the identification of a pharmacophore, we test here the notion that when a collective ensemble structural motifs, a “polymorphophore,” is incorporated into a molecule it renders the compound polymorphic. The structure–polymorphism relationship in six TA analogues, both commercial and newly synthesized, was undertaken with the intention of systematically understanding the factors that influence the polymorphism in the fenamic acid class through a combined computational as well as experimental approach. Ultimately, such studies may be used to experimentally derive the propensity for polymorphic behavior of a given molecular motif and perhaps provide a pathway to engineer molecular compounds with controlled properties in the solid state.