There are several factors that affect a patient's experience of pain. These include both local and systemic factors. The systemic factors that affect patients' dental and orofacial pain experience include, but not limited to, hormonal, nutritional, systemic infections, neurodegenerative, and autoimmune, among others. Comprehensive medical history is essential to delineate any possible systemic factors affecting pain experience. A thorough review of systems should form the foundation, since multiple factors can affect the prognosis of pain management. This would facilitate early recognition and trigger prompt referrals to the appropriate medical professionals. This helps to reduce the health care burden.