Over the last decades, functional imaging studies have fostered our knowledge of cerebral pain processing in humans. A lively interest has been focussing on possible opioidergic mechanisms of pain transmission and modulation. Today, reliable knowledge of the in vivo distribution of opioid receptors in healthy human subjects is available from positron emission tomography (PET) studies of opioidergic neurotransmission. Gender dependent differences in receptor distribution and ligand metabolism have been demonstrated. Moreover, an increasing number of studies are reporting alterations in receptor distribution patterns in states involving painful diseases. Various acute painful challenges have also been shown to induce measurable changes in receptor availability in multiple brain areas. The perigenual anterior cingulate cortex (ACC) has been identified as one brain region with a major impact on opioidergic pain modulation. Thereby, the ACC apparently executes cortical top-down control on brainstem structures in (exogenous) pharmacological opioid analgesia. In addition, accumulating evidence suggests that non-pharmacological treatment approaches also utilize similar endogenous opioid dependent pathways to exert pain modulation. This article summarizes our current knowledge of PET studies of the opioidergic system and outlines future perspectives.