Substance P (SP) is an endogenous tachykinin neuropeptide that is involved in inflammatory, pain, and stress signaling; it exhibits neuroprotective, cognition enhancing, and gastrointestinal motility modulating activities. SP is the natural ligand for the neurokinin-1 (NK1) receptor. In various animal models, SP modulates opioid signaling, induces gastric mucosal protection, and inhibits retinal apoptosis. SP also prevents hyperoxia-induced lung damage, decreasing levels of malondialdehyde and increasing levels of superoxide dismutase (SOD); this activity may be regulated through SHH signaling.