Chronic pain remains a significant clinical problem that has few effective therapies. Currently the success rate for treating chronic pain with analgesics is around 30%. Both treatment and research into chronic pain are greatly compromised by the fact that there is no objective diagnostic test that can complement the subjective assessment of chronic pain conditions. Chronic pain is now considered to be a disease of the central nervous system. Since behavior (including pain or analgesia) results from activity in brain circuits through the participation of many brain regions, we suggest that specific measures for the disease state and for drug effects can be defined using functional brain imaging. Tremendous advances have been made in functional imaging in the field of pain and analgesics and the development of CNS imaging biomarkers for pain may be close at hand. The successful identification of functional brain "signatures" for both drug action (analgesia) and disease state (neuropathic pain) when qualified could provide objective biomarkers to guide for drug development and clinical practice. In this two-part review, we discuss the potential of biomarkers for chronic pain including functional neuroimaging together with the challenges and limitations that are likely to be faced during the implementation of this strategy. The fit-for-purpose, scientific validation, and clinical qualification of novel CNS biomarkers for chronic pain could dramatically change the current outlook for treatment of chronic pain and research into its etiology.