The gabapentinoids (pregabalin and gabapentin) are first line treatments for neuropathic pain. They exert their actions by binding to the α2δ accessory subunits of voltage-gated Ca2+ channels. Because these subunits interact with critical aspects of the neurotransmitter release process, gabapentinoid binding prevents transmission in nociceptive pathways. Gabapentinoids also reduce plasma membrane expression of voltage-gated Ca2+ channels but this may have little direct bearing on their therapeutic actions. In animal models of neuropathic pain, gabapentinoids exert an anti-allodynic action within 30 minutes but most of their in vitro effects are 30-fold slower, taking at least 17 hours to develop. This difference may relate to increased levels of α2δ expression in the injured nervous system. Thus, in situations where α2δ is experimentally upregulated in vitro, gabapentinoids act within minutes to interrupt trafficking of α2δ subunits to the plasma membrane within nerve terminals. When α2δ is not up-regulated, gabapentinoids act slowly to interrupt trafficking of α2δ protein from cell bodies to nerve terminals. This improved understanding of the mechanism of gabapentinoid action is related to their slowly developing actions in neuropathic pain patients, to the concept that different processes underlie the onset and maintenance of neuropathic pain and to the use of gabapentinoids in management of postsurgical pain.