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 exhibits neuroprotective activity by decreasing expression of Kv1.4 K+ channels in transgenic animal models of Alzheimer’s disease and improving cognitive performance in the Morris water maze task. 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. In melanoma cells, SP decreases levels of tyrosinase and melanin, inhibiting melanogenesis. In other cellular models, SP increases the viability and proliferation of osteoblasts and promotes gap junction intracellular communication.