Pregabalin, which accesses the central nervous system (CNS) via the system L amino acid transporter and acts on the R2-δ subunit of voltage-gated calcium channels to attenuate calcium flux into neurons and the release of neurotransmitters like norepinephrine, substance P, and glutamate, has been approved for the treatment of neuropathic pain with the R2-δ hypothesis as its accepted mechanism of action (MOA). This Miniperspective showcases the medicinal chemistry efforts employed to obtain structurally diverse compounds with both reported affinity for the R2-δ subunit and in vivo activity in various neuropathic pain paradigms, including γ-amino acids (e.g., compound 3 with enhanced R2-δ potency and in vivo analgesic activity, compound 5 with increased R2-δ potency and conserved system L transport), β-amino acids (e.g., compound 11 showing anticonvulsant activity only via intracerebroventricular administration due to lack of system L affinity), α-amino acids (e.g., chlorinated phenylglycine 13 and (S)-benzylhomocysteine 14 effective in inflammatory pain models), carboxylate bioisosteres (e.g., tetrazole 23 demonstrating efficacy similar to pregabalin in chronic constriction injury (CCI) and incisional pain models, suppressing central sensitization), prodrugs (e.g., XP13512 with improved bioavailability), and non-amino acid structures (e.g., compound 26 effective in neuropathic pain models). It also presents experiments suggesting that R2-δ ligands act to suppress the development and maintenance of central sensitization (e.g., 23 preventing spinal wide dynamic range (WDR) neuron sensitization and prolonging analgesic effect when dosed prior to surgery) and discusses the implications of R2-δ subtype localization and function: studies with R217A mutant mice (deficient in R2δ-1 drug binding) indicate that binding to the R2δ-1 subtype is required for analgesic activity, while the distribution of R2δ-2 (dominant in cerebellum and brainstem) is associated with side effects like sedation and ataxia, suggesting that subtype-selective ligands may have unique therapeutic and side effect profiles compared to nonselective agents.