Development of new non-addictive pain medications requires advanced strategies to differentiate human induced pluripotent stem cells (iPSCs) into relevant cell types amenable for disease modeling and drug discovery. Here, we devised a highly efficient and scalable protocol that differentiates iPSCs exclusively into nociceptors under chemically defined conditions. By manipulating developmental pathways using small molecules, iPSCs were first converted into SOX10+ neural crest cells followed by differentiation into bona fide pseudo-unipolar BRN3A+ nociceptors. Detailed molecular and cellular characterization confirmed that differentiated nociceptors expressed typical neuronal markers, transcription factors, neuropeptides and over 150 ion channels and receptors. Focusing on pain-relevant receptors and channels expressed by iPSC-derived nociceptors (e.g. P2RX3, TRPV1, NAV1.7, NAV1.8), we demonstrated robust functional activities and differential response to noxious stimuli and specific drugs and demonstrate suitability for phenotypic screens. Lastly, a robotic cell culture system was used to automate the production of billions of cryopreservable cells for high-throughput drug screening, urgently needed to develop new nociceptor- selective analgesics and help to tackle the opioid crisis.