Temporomandibular disorders constitute a diverse group of pain conditions, usually presenting to the dental clinician with complaints of jaw tiredness, jaw pain, and dysfunction. Systemic conditions and factors can have a profound effect on the causality and the perpetuation of these pains. Dentists have a special position in the comprehensive care of these patients with a unique opportunity to screen for and initiate prompt medical referrals, thereby optimizing patient care. The focus of this review article is to explore the association between temporomandibular disorders (TMDs) and systemic factors such as arthritides, autoimmune diseases, endocrinological disorders, infections, sleep disorders, central sensitization syndromes, and drug- induced myalgia. The results suggest that systemic factors play an important role in initiating, perpetuating, and aggravating TMD pain, and making the pain resistant to conventional modalities of pain management. Further, these factors may have a causal relationship with pain. Systemic conditions such as arthritides, autoimmune disorders, anemias, chronic infections, thyroid disorders, and medication- induced myalgia seem to have the most impact. It may be desirable for the clinician attempting to manage TMDs and TMD pain to consider the effect of systemic factors on the pain experience of the patient.