Several hundred new synthetic drugs, novel psychoactive substances (NPS) or "legal highs" have in recent years appeared on the drug market. These can effortlessly be obtained from on-line vendors, offering an easy access to a plethora of new and untested substances, often with unknown or dangerous effects. Several different attempts to reduce the availability of NPS and to prevent accidents and fatalities have been applied by governments around the world. Nonetheless this complex and constantly evolving situation provides palpable dilemmas and challenges to legislators and prevention strategists. One unintended consequence from prohibition and current drug policies occurs when possibly more precarious substances are used to substitute older and more well-known illicit drugs; so called "substance displacement". We have performed extensive research on the use of NPS, by analyzing Internet resources (drug discussion forum, on-line questionnaires), and published several NPS studies. During our research we observed how substance displacement is a common issue, with implications for both clinical practices, drug prevention strategies, as well as for legislators. In the present review we discuss two common themes of substance displacement: 1) Synthetic cannabinoids replace herbal cannabis, and 2) Different attempts for self-medication using NPS. Incitements for substance displacement, that exposes the user to possibly more harmful substances, are founded both in legislation (availability of substances and fear of legal repercussions) as well as from certain policies or cultural perceptions of various medical conditions. We offer no obvious solutions to these complications, but would like to contribute to awareness of how these factors effects drug users and how measures intended to reduce harm in many cases have the opposite effects. Further studies on the divergent motivations and different groups of NPS users are highlighted as imperative to find new and realistic solutions going forward.