This chapter focuses on the voltage-gated sodium (Nav) channel and voltage-gated calcium channel (VGCC), since they are essential to pain transmission. The most basic structural plan of a eukaryotic voltage-gated ion channel consists of four sub-units surrounding a central pore, through which ions pass. Sodium channel inactivation is modulated by many factors, including toxins, disease states, mutations, and therapeutic drugs. In neurons, activation of VGCC in response to depolarized membrane potential leads to calcium entry, mediating calcium-dependent enzyme activation, gene expression, or release of neurotransmitters. Two main classes of VGCC have been reported, the T-type or low voltage activated (LVA) and the high voltage activated (HVA) channels. To manage different etiologies of neuropathic pain, a variety of therapeutic targets must be available. Drugs directed at specific targets, such as those channels expressed in nociceptors, or upregulated after injury, may give the best pain management while minimizing undesirable side effects.