Pain relief is a management problem for many patients, their families, and the medical professionals caring for them. Although everyone experiences pain to some degree, responses to it vary from one person to another. Recognizing and specifying someone else's pain is clinically a well know challenge. Research on the biology and neurobiology of pain has given us a relationship between spirituality and pain. There is growing recognition that persistent pain is a complex and multidimensional experience stemming from the interrelations among biological, psychological, social, and spiritual factors. Patients with pain use a number of cognitive and behavioral strategies to cope with their pain, including religious/spiritual factors, such as prayers, and seeking spiritual support to manage their pain. This article provides an overview of the complex phenomenon of pain, with a focus on spiritual and religious issues in pain management.