Epidural and intrathecal opioid administration has become an important part of contemporary medical practice in a variety of clinical settings. It has been widely assumed that any opioid placed in the epidural or intrathecal spaces will produce highly selective spinally mediated analgesia that is superior to that produced by other analgesic techniques. Unfortunately, this is simply not true. In fact, multiple opioids are currently employed for spinal use despite the fact that clinical evidence has shown that spinal administration does not produce analgesia with a selective spinal mechanism or that the analgesia produced is not superior to that produced by intravenous administration. This chapter presents the basic science and clinical data available to assist clinicians in identifying which opioids are appropriate for spinal use and which are not.