It is broadly accepted that, as part of the humane care and use of animals in research, the pain experienced by animals should be minimized to the extent possible, consistent with the goals of the research. In some cases, pain may be the subject under study, whereas in other cases, the use of some types of analgesics may interfere with the experimental objectives of the work. This issue of Comparative Medicine provides reviews related to the recognition and treatment of pain, the interaction of pain and pain relief on experimental outcomes, and ethical perspectives on the need to reduce pain in research rodents, whenever possible.