Gain-of-function mutations in SCN9A, which encodes the sodium channel Nav1.7 (expressed in the peripheral nervous system), has a crucial role in a chronic pain disorder, inherited erythromelalgia (IEM). Here, Cao et al. demonstrate that iPSC-derived sensory neurons (iPSC-SNs), generated from four patients with IEM carrying different SCN9A mutations, exhibit elevated excitability and increased sensitivity to heat compared with iPSC-SNs from non-IEM donors. The increased excitability and sensitivity of these neurons were reduced by the novel selective Nav1.7 blocker PF-05089771. A single oral dose of PF-05089771 decreased heat-induced pain in 4 out of 5 patients with IEM.