Endogenous pain regulatory system dysfunction appears to play a role in the maintenance of chronic pain. An important component of the pain regulatory process is the functional interaction between the cardiovascular and pain regulatory systems, which results in an association between elevated resting blood pressure (BP) and diminished acute pain sensitivity. This BP/pain sensitivity relationship is proposed to reflect a homeostatic feedback loop helping restore arousal levels in the presence of painful stimuli. Evidence is emerging that this normally adaptive BP/pain sensitivity relationship is significantly altered in chronic pain conditions, affecting responsiveness to both acute and chronic pain stimuli. Several mechanisms that may underlie this adaptive relationship in healthy individuals are overviewed, including endogenous opioid, noradrenergic, and baroreceptor-related mechanisms. Theoretical models are presented regarding how chronic pain-related alterations in the mechanisms above and increased pain facilatory system activity (central sensitization) may contribute to altered BP/pain sensitivity interactions in chronic pain. Clinical implications are discussed.