New psychoactive substances (NPS) are a challenge for the worldwide forensic community. More than 450 NPS are currently being monitored by the UNODC and EMCDDA. NPS are a major challenge for laboratories, not only because of the large numbers of NPS, but also due to the continuous chemical development of the substances and thus the rapid turnover of the drug market. The aims of our publication are to give an overview of practical considerations when applying oral fluid (OF) analysis in the context of NPS detection, to highlight the current limitations and to address options to improve current research and legislative actions. OF sample collection and protocols will be discussed as differences will have an impact on the final obtained concentrations via dilution, drug (in)stability and recovery issues. In addition, the current state and the future possibilities for NPS detection in OF using direct assays or chromatographic techniques are described. Finally, judicial challenges and applications are discussed.