Pain is not simply due to the activation of peripheral nociceptors but to multiple factors. Part of the article is a review of scientific work on such factors at the different levels of the peripheral and central nervous system, with particular reference to possible new therapy strategies. A second part describes some aspects of clinical assessment of persistent pain conditions, such as differential diagnostics between musculoskeletal nociceptive and neurogenic pain, between referred pain from a musculoskeletal focus and projected neurogenic pain, and between psychogenic pain and pain with a somatic cause.