Introduction: Drug abuse is a worldwide crisis, and illicit drug testing is widely applied daily both clinically and forensically. Gas chromatography- mass spectrometry (GC-MS) is the traditional confirmatory gold standard for drug testing and is used for non-targeted substance screening, however, it is limited to volatile non-polar compounds. Liquid chromatography- tandem MS (LC-tandem-MS) has become a new gold standard for its ability to identify more types of analytes (polar and non-polar). In contrast to GC-MS, it is not suited for non-targeted drug screening as different optimal parameters are set for each drug. Aim: Describe the advanced techniques for testing illicit substances and then, recommend the most appropriate ones for point of care (POC) settings. Results: High-resolution-MS (HRMS) such as time of flight MS (Tof-MS), made the analysis of compounds of same molecular masses but with different formulas possible. Quadrupole Tof-MS is suited for non-targeted substance screening. Another novel technology is the emergence of miniature ambient ionization MS, that is portable and can analyze unprepared samples in native environment within one minute. Ion mobility spectrometer (IMS) is another advance that can identify compounds including isomers with high resolution within seconds and portable devices are available. Portable Raman and near infrared (NIR) spectrometers have allowed fast screening for drugs and have been efficiently used for other on-site forensic applications. Hence, these advanced techniques are promising for quick detection of illicit drugs in a POC setting. Conclusion: HRMS is an accurate comprehensive method for qualitative and quantitative testing in laboratory settings. Miniature ambient ionization MS is very rapid with no sample preparation, but it is more expensive than other alternatives in POC testing. Thus, the best methods for POC drug testing are portable IMS, portable Raman spectrometer, and handheld NIR spectrometer for their accurate, easy, and quick analysis within seconds with affordable costs.