I will present work we have pursued to identify key mechanisms explaining aberrant pain processing by the nervous system as well as co-morbidities that develop from sustained pain hypersensitivity. This includes the discovery of impaired inhibition resulting from chloride dysregulation in neuropathic pain conditions, leading to crosstalk between sensory channels, a probable substrate of abnormal touch-evoked pain (allodynia), and ectopic activity, possibly underlying spontaneous pain. I will illustrate how such discovery opens new perspectives to understand pathological pain and how it affects our thinking for therapeutic design. Disrupted chloride homeostasis is now emerging as a common pathway to several brain disorders, including transition to addiction, and maladaptive responses to opioid treatment. I will conclude on recent evidence that chloride dysregulation can also be a key target for prevention, and perhaps reversal of neurodegenerative disorders, in particular ALS and Alzheimer’s disease.