Misuse of prescription opioid medications has continued as a major public health problem in the United States. Review of major epidemiologic databases shows that the prevalence of opioid misuse rose markedly through the 1990s and the early part of the current decade. In this same period of time, the number of prescriptions for chronic noncancer pain increased markedly, and the intersection of these two public health problems remains a concern. Further, despite some leveling off of the overall rate of prescription opioid misuse in the past several years, surveillance data show high and increasing mortality associated with these drugs. Analysis of the 2006 National Survey of Drug Use and Health indicates the increasing prevalence of prescription opioid misuse is associated more with an increase in the general availability of these medications than misuse of the medications by those who were directly prescribed them. National Institute on Drug Abuse initiatives to address the prescription opioid problem include programs to stimulate research in the basic and clinical sciences, and to educate physicians and other health personnel.