Pain is a complex, multidimensional experience that has defied our understanding for centuries. Through the advent of noninvasive neuroimaging techniques, we have been able to examine the human brain and its response to nociceptive inputs. As a result, our knowledge of which brain regions are critical for generating an acute pain experience has grown, as has our understanding of how cognitive, emotional, contextual and various physiological factors influence the pain experience. Furthermore, we have been able to identify key processes within the brain that underpin the transition to and maintenance of chronic pain states, as well as highlight the dramatic consequences of chronic pain on the brain's structure and neurochemistry. Building upon this knowledge, we are now in a position to consider whether any of these brain imaging 'phenotypes' of acute or chronic pain should be considered as useful endophenotypes; thereby enabling us to relate the complex genetics that underpin everyday pain sensitivity or chronic pain states to intermediate biomarkers. This endophenotypic approach-the focus of this Review-simplifies the connection between genes and behavior and is needed for complex disorders like chronic pain.