Drugs originate from the discovery of compounds, natural or synthetic, that bind to proteins (receptors, enzymes, transporters, etc.), the interaction of which modulates biological cascades that have potential therapeutic benefit. Rational strategies for identifying novel drug therapies are typically based on knowledge of the structure of the target proteins and the design of new chemical entities that modulate these proteins in a beneficial manner. The present review discusses a novel approach to drug discovery based on the identification and characterization of auxiliary proteins, the transmembrane AMPA receptor regulatory proteins (TARPs) that are associated with AMPA receptors. Utilizing these auxiliary proteins in compound screening led to the discovery of the TARP-dependent-AMPA forebrain selective receptor antagonist (TDAA), LY3130481/CERC-611 that is currently in clinical development for epilepsy.