UNLABELLED: Altered function of endogenous pain modulation has been proposed as a mechanism that may underlie chronic pain conditions. Descending modulation of pain can be examined by diffuse noxious inhibitory controls (DNIC). DNIC comprises a spinal-medullary-spinal pathway that is activated when 2 concomitant painful stimuli are applied at the same time. This pain-inhibitory system can be easily triggered in an experimental setting. Therefore, studies on DNIC can help us to evaluate impairments in descending pain modulation, presumably primarily of inhibitory nature. This review summarizes recent findings on human DNIC trials with a specific focus on sex, age, and ethnic differences in DNIC effects and psychological mediators such as attention, expectation, and pain catastrophizing. Furthermore, the clinical relevance of DNIC studies will be discussed. Different methodological approaches used make it difficult to generalize results, but the research to date has shown good potential for DNIC to help in gaining insights in the underlying mechanisms of chronic pain conditions. PERSPECTIVE: Recent literature on diffuse noxious inhibitory controls as a model of endogenous pain modulation in clinical pain syndromes was reviewed. DNIC may help to identify patients at risk for development of chronic pain and may open alternatives for treatment options.