The recreational use of synthetic cannabinoids, or commonly termed as synthetic cannabinoid receptor agonists (SCRAs), is increasing globally in the last decade. These synthetic compounds are more potent than the Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabis, causing toxic effects and fatality among users. SCRAs do not cross-react with the antibody used for screening of cannabis metabolites in urine. Moreover, potential presence of SCRAs in urine is not targeted in many drug testing laboratories during workplace drug testing, leading to non-detection of SCRA misuse. Due to the large number and evolving nature of SCRAs emerged in the black drug market, detection of SCRA misuse represents a significant analytical challenge for drug testing laboratories world-wide. This challenge is exacerbated by the lack of metabolism data for many SCRAs, especially the newer ones, and the lack of commercially available reference standards for them. To overcome the analytical challenge, a paradigm shift towards untargeted screening strategies using mass spectrometric tools, especially the high-resolution mass spectrometry (HRMS) technique, is warranted. Rapid and effective identification of metabolic pathways of SCRAs remains crucial in searching for unique metabolites of SCRAs for monitoring SCRAS misuse.