Chronic pain syndromes affect up to 20% of the population, impose significant suffering and are often resistant to available treatments (1, 2). Refractory chronic pain was among the first studied indications for brain stimulation over 50 years ago (3, 4). Deep brain stimulation (DBS) involves the reversible modulation of neural function by delivering electrical pulses to specific brain circuits through surgically implanted electrodes, which are connected to an implanted pacemaker device. Despite high rates of success reported in case reports and series using DBS for chronic pain, two large, suboptimally designed clinical trials failed to meet primary endpoints in the 1990’s (5). As a result, DBS for pain has been relegated to “off-label” or experimental use around the world, with no clear consensus on optimal brain targets, pain indications, or patient selection. To date, there has only been one rigorous, double-blinded randomized control trial testing DBS efficacy for chronic pain, which also failed to meet its primary endpoint (6). In parallel with a growing understanding of brain mechanisms for chronic pain in the last decade (7), DBS has undergone significant technological and scientific advancements for the treatment of approved neurological disorders such as epilepsy or Parkinson’s disease. This Research Topic aims to integrate emerging insights into brain mechanisms of pain towards advancing DBS as viable therapy for chronic pain syndromes. Pagano et al. reviewed the history of target selection for DBS, with a focus on the translational connection between preclinical and clinical studies. The periaqueductal/periventricular gray matter and sensory thalamic nuclei are considered classical targets, typically for the treatment of nociceptive and neuropathic pain syndromes, respectively. The authors review potential explanations for high variability of results between different preclinical and clinical studies, including the complexity of pain and the potential involvement of multiple networks (Figure 1). There has been a more recent focus on targeting the affective and emotional components of pain with stimulation of the anterior cingulate cortex or the ventral