In this hybrid review, we have first collected and reviewed available information on the structure and function of the enigmatic cache domains in α2δ proteins. These are organized into two double cache (dCache_1) domains, and they are present in all α2δ proteins. We have also included new data on the key function of these domains with respect to amino acid and gabapentinoid binding to the universal amino acid–binding pocket, which is present in α2δ-1 and α2δ-2. We have now identified the reason why α2δ-3 and α2δ-4 do not bind gabapentinoid drugs or amino acids with bulky side chains. In relation to this, we have determined that the bulky amino acids Tryptophan and Phenylalanine prevent gabapentin from inhibiting cell surface trafficking of α2δ-1. Together, these novel data shed further light on the importance of the cache domains in α2δ proteins.