Until recently it has been difficult to obtain reliable objective information from normal subjects and patients regarding their subjective pain experience. Relating specific neurophysiologic markers to perceptual changes induced by peripheral or central sensitisation, behavioural, psychological or pharmacological mechanisms and identifying their site of action within the CNS has been a major goal for scientists, clinicians and the pharmaceutical industry. This information provides a powerful means of understanding not only the central mechanisms contributing to the chronicity of pain states but more importantly potential diagnostic information (1). Identifying non-invasively where plasticity, sensitisation and other amplification processes might occur along the pain neuraxis for an individual and relating this to their specific pain experience or measure of pain relief has considerable value. It allows a better understanding of what drives and maintains their pain state thereby allowing more appropriate selection and targeting of treatment options. With the advent of functional neuroimaging methods, such as functional magnetic resonance imaging (FMRI), positron emission tomography (PET), electroencephalography (EEG) and magnetoencephalography (MEG) this has been made feasible. Robust and reproducible activation in response to nociceptive stimulation within the human brain and spinal cord has been shown. This activation, often considered an “objective” readout of the subjective phenomenon, can be related to what the subject describes, allowing issues such as how anxiety, depression, attention, etc. alter a pain perception to be better understood at a neuroanatomical level. This provides not only potential diagnostic information but also targets for intervention. Over the past ten years, we have performed several experiments that have specifically isolated areas of cortex and brainstem that are central to the processes of expecting pain, being anxious or depressed about pain and altering your attention to pain (2-4). Furthermore, the central relevance of descending brainstem modulatory pathways in the generation and maintenance of chronic pain states in clinical conditions is becoming increasingly accepted. Advances in our ability to image this challenging area have been developed in our laboratory (5, 6) and many examples of dysfunction in this system are now found across various chronic pain conditions (7). More recently, pharmacological functional magnetic resonance imaging (phMRI) has been developed and applied to the field of pain research within our laboratory (8). Again, many advances have been made that illustrate the neural correlates of analgesia in the human brain (9). New thoughts related to how pain and pleasure interact force us to broaden our understanding of relief mechanisms and well-being (10). Finally, recent advances in our ability to image functional activation in the human spinal cord show considerable promise and provide a novel and exciting area of further investigation (11). In summary, functional imaging methods provide a powerful means to directly examine pain mechanisms in human subjects and patients at a systems level, providing potential diagnostic information as well as identifying targets for therapeutic intervention. 1. Schweinhardt P, Lee M, Tracey I. Curr Opin Neurol. 2006;19(4):392-400. Review. 2. Ploghaus A, Narain C, Beckmann CF, Clare S, Bantick S, Wise R, Matthews PM, Rawlins JN, Tracey I. J Neurosci. 2001;21(24):9896-903. 3. Ploghaus A, Tracey I, Gati JS, Clare S, Menon RS, Matthews PM, Rawlins JN. Science. 1999;284(5422):1979-81. 4. Schweinhardt P, Kalk N, Wartolowska K, Chessell I, Wordsworth P, Tracey I. Investigation into the neural correlates of emotional augmentation of clinical pain. Neuroimage. 2007; [Epub ahead of print] 5. Dunckley P, Wise RG, Fairhurst M, Hobden P, Aziz Q, Chang L, Tracey I. J Neurosci. 2005;25(32):7333-41. 6. Lee MC, Zambreanu L, Menon DK, Tracey I. J Neurosci. 2008;28(45):11642-9. 7. Tracey I, Mantyh PW. Neuron. 2007;55(3):377-91. Review. 8. Schweinhardt P, Bountra C, Tracey I. NMR Biomed. 2006;19(6):702-11. 9. Iannetti GD, Zambreanu L, Wise RG, Buchanan TJ, Huggins JP, Smart TS, Vennart W, Tracey I. Proc Natl Acad Sci U S A. 2005;102(50):18195-200. 10. Leknes S, Tracey I. Nature Reviews Neuroscience. 2008; 9(4):314-20 11. Brooks JC, Beckmann CF, Miller KL, Wise RG, Porro CA, Tracey I, Jenkinson M. Neuroimage. 2008;39(2):680-92.