Chronic pain is one of the most difficult problems facing medicine and the neurosciences. Through the centuries, it has been a puzzle and still remains a challenge for research, given its complex nature. We can study it as a fluid system composed of interacting networks, the so-called “Pain Matrix”, bearing in mind that pain is the result of the continuous interaction of subsystems or networks. This assumes that major changes in the painful experience and cortical plasticity do not depend only on the action and interaction of dynamic brain networks but also on communication between the brain and external networks, such as socio-cultural factors modulating the perception of pain. The painful perception thus depends on a variety of external and internal influences independent of the nociceptive input. 1 CortiCal PlastiCity related to ChroniC Pain In this paper, I will explore the cortical mechanisms of physiological chronic pain as well as its cognitive and emotional components, pointing out that brain activity differs between acute and chronic pain and emphasizing the difference between pain and suffering. I contend that internal and external networks are interlinked, and I address the issue of chronic pain as a neuro-mental mechanism with neurobiological bases and as a subjective and qualitative mind experience, leading me to propose a new definition of chronic pain. Consequently, this paper is a discussion of the rationale and evidence for cortical reorganization as a consequence of chronic pain, and for the interaction between the neuronal and mental processes that modulate the aversive emotional component of chronic pain perception.