The gate control theory of pain, introduced by Melzack and Wall in 1965, led the way in pain research during the second half of the 20th century. Eventually, the observation of pain-related phenomena which the theory could not satisfactorily explain propelled Melzack to develop a new concept, the neuromatrix, which considers as participants in the pain transmission and modulation system, certain brain areas not traditionally associated with the pain experience. This concept places equal importance on the sensory, affective and cognitive aspects of pain, helping the advancement of novel diagnostic and therapeutic approaches in different clinical pain conditions.