The concept of rational polypharmacy is now well established in the field of pain management. This concept has evolved in concert with progress in understanding the pathophysiologic mechanisms of pain diseases and disorders and how medications affect these processes. Other clinical factors must be considered in formulating the pain management strategy most likely to succeed in both controlling pain and improving function in a given patient. This article will review how pain diagnosis, pain mechanisms, pain phenomenology, medication efficacy, and risk profile influence medication selection in pain medicine practice, with a selective focus on the treatment of neuropathic pain. In addition, the role of psychosocial factors as they affect pain management will be discussed.