Of all clinically marketed drugs, greater than thirty percent are modulators of G protein-coupled receptors (GPCRs). Nearly 400 GPCRs (i.e., excluding odorant and light receptors) are encoded within the human genome, but only a small fraction of these seven-transmembrane proteins have been identified as drug targets. Chronic pain affects more than one-third of the population, representing a substantial societal burden in use of health care resources and lost productivity. Furthermore, currently available treatments are often inadequate, underscoring the significant need for better therapeutic strategies. The expansion of the identified human GPCR repertoire, coupled with recent insights into the function and structure of GPCRs, offers new opportunities for the development of novel analgesic therapeutics.