This paper reviews high-resolution MS approaches published from January 2011 until March 2014 for the quantification of drugs (of abuse) and/or their metabolites in biosamples using LC-MS with time-of-flight or Orbitrap™ mass analyzers. Corresponding approaches are discussed including sample preparation and mass spectral settings. The advantages and limitations of high-resolution MS for drug quantification, as well as the demand for a certain resolution or a specific mass accuracy are also explored.