Today, the use of hair analysis for forensic issues concerning drugs collectively indicated as NPS is still controversial. In particular, little is known about the incorporation into the keratin matrix after intake and the correlation between their dosage, passive exposure, use frequency, and hair concentrations. In the present review, we considered the main issues, which still deserve substantial research and discussion within the scientific community, before a definitive interpretation of either a positive or negative results can be safely given to the local authorities. Specifically, the following scenarios were considered: (i) passive exposure vs. active consumption, (ii) mindful vs. unaware intake, and (iii) sporadic vs. chronic use. Differently from the traditional drugs of abuse, whose chemical and toxicological properties have been largely elucidated, in the context of NPS the range of chemical structures is so various that it is difficult to speculate about general criteria. Under these circumstances, any analytical outcome from NPS hair analysis should be cautiously interpreted by experienced forensic toxicologist.