Chronic orofacial pain syndromes are produced by nerve injury, diseases, and toxins. They constitute an unsolved medical problem because they affect a considerable number of adults and are difficult to treat. There is a remarkable variability among adults in terms of susceptibility to chronic orofacial pain and its characteristics, which suggests that these syndromes are complex heritable traits controlled by alleles of certain polymorphic genes that interact with the environment. Each syndrome is assumed to be determined by a unique set of genes. In the present report, a practical study design is proposed to identify the genes responsible for interindividual variability in orofacial pain levels. This design is based on research strategies that have been used for studying other human diseases as well as pain syndromes outside the orofacial region. Specifically, this design has been used successfully by the authors and others over the past 8 years to study chronic pain syndromes such as migraines, radiculopathy, amputation pain, and postmastectomy pain. The strategies used to study these topics have been adapted to address the unique problems of orofacial pain. The authors believe that the study of genetics provides a novel research approach from which to identify targets for the development of individually tailored approaches in orofacial pain medicine, such as diagnostic and prognostic kits and novel drugs that would prevent pain chronicity in susceptible individuals or alleviate it once it had developed. This report focuses on human models. A follow-up report is intended to extend this design into animal models of orofacial pain syndromes.