This chapter considers the available routes for systemic administration of analgesic drugs before presenting the evidence for advantage of one route of administration over another for both nonopioid and for opioid analgesic drugs. The techniques of intranasal and inhalation administration of dried plant extracts followed the discovery of tobacco. Although the routes of administration of drugs continued to evolve up until the end of the twentieth century, more attention has focused on developing new formulations and mechanisms for enhancing drug delivery. The oral route is the most commonly used route of administration and is the route of choice so long as the gastrointestinal tract is intact and the patient is able to take fluids by mouth. Rectal administration results in absorption directly into the systemic circulation, with resultant greater drug bioavailability. Rectal administration is associated with a slow onset of effect which may be influenced by patient factors, as well as formulation.