The voltage-gated sodium channel isoform Na<sub>V</sub>1.7 has drawn widespread interest as a target for non-opioid, investigational new drugs to treat pain. Selectivity over homologous, off-target sodium channel isoforms, which are expressed in peripheral motor neurons, the central nervous system, skeletal muscle and the heart, poses a significant challenge to the development of small molecule inhibitors of Na<sub>V</sub>1.7. Most inhibitors of Na<sub>V</sub>1.7 disclosed to date belong to a class of aryl and acyl sulfonamides that preferentially bind to an inactivated conformation of the channel. By taking advantage of a sequence variation unique to primate Na<sub>V</sub>1.7 in the extracellular pore of the channel, a series of bis-guanidinium analogues of the natural product, saxitoxin, has been identified that are potent against the resting conformation of the channel. A compound of interest, <b>25</b>, exhibits >600-fold selectivity over off-target sodium channel isoforms and is efficacious in a preclinical model of acute pain.