Non-invasive functional brain imaging is used more than ever to investigate pain in health and disease, with the prospect of finding new means to alleviate pain and improve patient wellbeing. The observation that several brain areas are activated by transient painful stimuli, and that the magnitude of this activity is often graded with pain intensity, has prompted researchers to extract features of brain activity that could serve as biomarkers to measure pain objectively. However, most of the brain responses observed when pain is present can also be observed when pain is absent. For example, similar brain responses can be elicited by salient but non-painful auditory, tactile and visual stimuli, and such responses can even be recorded in patients with congenital analgesia. Thus, as argued in this review, there is still disagreement on the degree to which current measures of brain activity exactly relate to pain. Furthermore, whether more recent analysis techniques can be used to identify distributed patterns of brain activity specific for pain can be only warranted using carefully designed control conditions. On a more general level, the clinical utility of current pain biomarkers derived from human functional neuroimaging appears to be overstated, and evidence for their efficacy in real-life clinical conditions is scarce. Rather than searching for biomarkers of pain perception, several researchers are developing biomarkers to achieve mechanism-based stratification of pain conditions, predict response to medication and offer personalized treatments. Initial results with promising clinical perspectives need to be further tested for replicability and generalizability.