What are the mechanisms of pain chronification? Are they different than those of acute pain? Answering these questions is not only critical for the basic understanding of chronic pain, which is one of the leading causes of years lived with disability but are also necessary to avoid treating chronic pain patients with opioids, which currently represent one of the major causes of drug addiction. I will summarize recent evidence pointing to functional reorganization of the limbic system as a key factor in pain chronification. I will show how such reorganization is critical for the cognitive symptoms of chronic pain, but also for sensory pain perception. In particular, I will focus on the complex reorganization of the medial prefrontal cortex-nucleus accumbens network as a major locus for the transition from acute to chronic pain and show how understanding these mechanisms may pave the way to new opioid-independent therapeutic approaches.