Pain is a worldwide chronic health issue, and additional therapies are needed for the management of severe pain. Substance P-Saporin (SP-SAP) covalently links a biological toxin (SAP) and an endogenous peptide (SP) that targets that toxin to the subset of neurons expressing the NK1 receptor. SP-SAP, currently in phase I clinical trials, is unique as the only targeted toxin for pain to undergo human testing.We review the history of SP-SAP and related NK1-receptor targeted toxins. We review animal data on the safety and efficacy of SP-SAP for the treatment of pain in light of the results of NK1 receptor antagonists and knockouts/knockdowns of either SP or the NK1 receptor. Finally, we discuss possible mechanisms of action of SP-SAP.