Attempts to curtail substance use problems have been directed at their virtually every aspect, from interdicting illegal drugs to investments in biomedical research. The problems’ persistence, however, including but not limited to the latest “opioid epidemic,” suggests that these costly measures have not resulted in a stable improvement in the past and do not promise lasting success in the future. Translation of research results, pertaining mainly to the factors that elevate risk and lead to disorder, has not been satisfactory. A review of relevant facts in the first of two connected articles indicates the need for changes in approaches to substance use and lays foundation to methodological research design protocols described in the second paper.