In this review we outline the actions of gabapentin and pregabalin on the excitability of sensory dorsal root ganglion (DRG) neurones in culture and compare these effects with those seen in other neuronal and cultured cell preparations. We also consider the potential mechanisms of action of gabapentin and pregabalin that may contribute to their anti-nociceptive effects. Gabapentin and pregabalin have similar actions and at saturating concentrations do not have additive effects suggesting that they act at the same or closely associated sites. The only high affinity binding sites yet identified for these drugs are α2δ-subunits (types 1 and 2 but not 3 and 4) of voltage-activated Ca2+ channels. Consistent with this are the findings that gabapentin and pregabalin both attenuate Ca2+ influx through voltage-activated channels and these inhibitory actions may in part provide a mechanism by which multiple firing of action potentials in sensory neurones is reduced. However, it is clear that gabapentin and pregabalin have a number of novel characteristics. Although structural analogues of GABA they appear to act independently of GABA receptor activation in sensory neurones. The actions of gabapentin and pregabalin on sensory neurones are not consistent with selective effects on particular high voltage-activated Ca2+ channel subtypes (L, N, P, Q and R) yet a significant proportion (at least 50%) of the whole cell Ca2+ current is insensitive to these drugs. Cell culture conditions can alter Ca2+ channel subunit expression in such a way as to reduce sensitivity to gabapentin and this can be used to identify potential sites of action of this drug. Analysis of subunit mRNA in cell populations with different sensitivities to gabapentin surprisingly indicated that Ca2+ channel b2-subunits as well as α2δ-subunits may determine Ca2+ channel sensitivity to gabapentin in DRG neurones. In addition to Ca2+ channels, gabapentin and pregabalin modulate other whole cell currents, and in particular a delayed enhancement of voltage-dependent K+ conductances has been observed in cultured DRG neurones. The delayed and prolonged features of this enhancement of voltage-activated K+ currents may reflect gabapentin and pregabalin modulating channel activity via intracellular signalling pathways either via a surface receptor interaction leading to the production of a second messenger or by directly acting at intracellular sites. The wide variety of therapeutic effects achieved with gabapentin and pregabalin offer a considerable challenge when trying to determine cellular mechanisms of action of these apparently simple synthetic compounds.