Substance P (SP) is a highly conserved member of the tachykinin peptide family that is widely expressed throughout the animal kingdom. The numerous members of the tachykinin peptide family are involved in a multitude of neuronal signaling pathways, mediating sensations and emotional responses (Steinhoff et al. in Physiol Rev 94:265-301, 2014). In contrast to receptors for classical transmitters, such as glutamate (Parsons et al. in Handb Exp Pharmacol 249-303, 2005), only a minority of neurons in certain brain areas express neurokinin receptors (NKRs) (Mantyh in J Clin Psychiatry 63:6-10, 2002). SP is also expressed by a variety of non-neuronal cell types such as microglia, as well as immune cells (Mashaghi et al. in Cell Mol Life Sci 73:4249-4264, 2016). SP is an 11-amino acid neuropeptide that preferentially activates the neurokinin-1 receptor (NK1R). It transmits nociceptive signals via primary afferent fibers to spinal and brainstem second-order neurons (Cao et al. in Nature 392:390-394, 1998). Compounds that inhibit SP's action are being investigated as potential drugs to relieve pain. More recently, SP and NKR have gained attention for their role in complex psychiatric processes. It is a key goal in the field of pain research to understand mechanisms involved in the transition between acute pain and chronic pain. The influence of emotional and cognitive inputs and feedbacks from different brain areas makes pain not only a perception but an experience (Zieglgänsberger et al. in CNS Spectr 10:298-308, 2005; Trenkwaldner et al. Sleep Med 31:78-85, 2017). This review focuses on functional neuronal plasticity in spinal dorsal horn neurons as a major relay for nociceptive information.