Potassium (K+) channels play a critical role in regulating neuronal excitability, a fundamental feature of pain. The opening of K+ channels leads to hyperpolarization of the cell membrane, which results in a decrease of cell excitability. In the nociceptive pathways, K+ channels are involved in a number of processes within the nervous system, including neuronal depolarization, axonal conduction, and neurotransmitter release. As a consequence of the role played by K+ channels in the regulation of the nociceptive system and that K+ channel opening is involved in the antinociception induced by numerous analgesic drugs they have begun to be considered as direct targets for the development of new antinociceptive therapies. A limited number of potential K+ channels have, so far, been identified as targets for the development of antinociceptive therapies. This review considers the potential of selective modulators of KCNQ, KATP, GIRK, Twopore domain K+ channels, or KCa channels as novel therapeutic approaches to pain. Structure-activity relationship (SAR) studies to identify K+ channel selective modulators to target neuroexcitability and pain have, however, been limited to modulators KCNQ channels. The scope of the field of K+ channel modulators is just emerging but demonstrates promise for novel therapeutics in the management of pain.