"Diffuse noxious inhibitory controls" (DNIC) refer to the observation that the activity of multi-receptive neurons of the spinal cord and trigeminal system can be strongly suppressed by an intensive pain stimulus outside their peripheral receptive field. This effect represents a neurophysiologically well-established animal model of endogenous pain modulation that has been consistently demonstrated across different species. Electrophysiological and anatomical data support the view that DNIC are sustained by a largely independent spino-bulbo-spinal loop that critically involves the caudal medulla. It is assumed that, corresponding to the animal model, the perceptive effects of 'heterotopic noxious conditioning stimulations' (HNCS) in humans are predominantly based on the DNIC mechanism. This review focusses on DNIC and HNCS including similarities, divergences and their potential clinical relevance.