The peripheral nervous system (PNS) is designed to receive inputs from the environment and transduce these into signals that are sent to the central nervous system (CNS). While most PNS neurons carry some receptors for classical neurotransmitters like glutamate, they are only weakly sensitive to these substances (or are not nearly as sensitive to them as CNS neurons are). Instead, as their primary function is to detect changes in external cues—for instance, heat and foreign chemicals—they are thought to be activated mostly through a broad range of receptors that recognize such environmental signals. These receptors can be divided into several broad groups. The groups comprising the olfactory and taste receptors represent the classic examples of families that, taken together, can detect an extraordinary range of substances from the environment. Both groups are members of the GPCR superfamily and are coupled to various G-proteins, through which they transduce their signals in second messenger mediated intracellular pathways. Each receptor is “tuned” to respond to varying degrees to chemicals with specific structures or properties. Many of these receptors exist—several dozen olfactory receptors in humans and several hundred in mice—and each is tuned differently. The circuitry underlying detection of odors is complex and knowledge of it is incomplete, though the field is moving forward rapidly, but it is thought that specific odors are detected by CNS processing of the signals sent from many different olfactory neurons that respond differently to the same odor. The ensemble input is different for every odor; in such a way, this library of receptors is capable of detecting a vast array of substances not ever made endogenously.Among the sensations detected by the PNS, arguably the ones that induce the quickest behavioral (as opposed to motor) responses are those of pain and itch. These unpleasant sensations direct the organism to avoid a harmful situation or to remove a dangerous animal like a parasite. Like olfaction and taste, they are critical for survival, though extended experience of these sensations, often occurring in pathological states, dramatically lowers quality of life. It is known that mechanical stimulation and a wide range of chemicals can induce these sensations. While receptors have been discovered for several individual chemicals—one example is the TrpV1 channel for the neurotoxin capsaicin—other mechanisms must be discovered to account for the effects of most painful and itchy substances. One attractive hypothesis is that the neurons innervating the epithelia employ a family of receptors, analogous to the olfactory system, that serve to detect these noxious stimuli.The Mrgpr family of receptors was discovered in 2001 and comprises 18 genes and pseudogenes in humans and 50 in mice (Dong et al. 2001) (Figure 12.1a). Many members are expressed exclusively in the dorsal root ganglia (DRG) and trigeminal ganglia (TG), which extend neurites into several layers of the skin and are responsible for most peripheral sensations, including noxious mechanical stimuli and temperature (Dong et al. 2001) (Figure 12.1b). This expression pattern raises the exciting possibility that they are specialized for somatosensation. In 2009, one of these receptors was found to be critical for the itch induced by the antimalarial drug chloroquine (Liu et al. 2009). In this and other studies, other pruritic substances were also shown to activate Mrgpr family members, further linking them to itch sensation (Liu et al. 2009, 2011). At the moment, it is unclear whether most pruritic stimuli act through these receptors, at least indirectly, but they have helped clarify the neural mechanisms underlying itch, and to a lesser extent, pain sensation. The history of research on Mrgprs is presented here, including what is known currently about this interesting family of receptors.