During the last few years, the rapid emergence of novel psychoactive substances (NPS) has significantly reshaped the global drug scene. Emergency hospital admissions and confirmed or suspected NPS-related deaths are on the rise, and many related health and social problems may have not yet even been fully recognised. Potential NPS harms stem from the lack of information, as well as from the general sets and settings of drug use. As compared with “classical” drug harm reduction, NPS-related harm reduction has got a notably more difficult operational environment. In this chapter, I will briefly outline the emergence, terminology, and appeal of the NPS phenomenon, and introduce a seven-item list of NPS-related risks and subsequent potential harms that has been compiled from both academic and anecdotal sources. Moreover, I summarise six important ongoing NPS harm reduction attempts that can be currently perceived as best-practices, illustrated by European examples. Finally, I conclude the analyses of NPS-related harms and harm reduction best-practices by discussing some conceptual, strategic, practical, and drug policy issues.