The use of liquid chromatography-mass spectrometry (LC-MS) has recently exploded in various analytic fields, including toxicology and therapeutic drug monitoring (although still far behind pharmacokinetics). There is no doubt that LC-MS is currently competing with gas chromatography (GC)-MS for the status of the reference analytic technique in toxicology. This review presents, for the nonspecialist reader, the principles, advantages, and drawbacks of LC-MS systems using atmospheric pressure interfaces. It also gives an overview of the analytic methods for xenobiotics that could be set up with these instruments for clinical or forensic toxicology. In particular, as far as quantitative techniques are concerned, this review tries to underline the large number and variety of drugs or classes of drugs (drugs of abuse, therapeutic drugs) or toxic compounds (e.g., pesticides) that can be readily determined using such instruments, the respective merits of the different ionization sources, and the improvements brought about by tandem MS. It also discusses new applications of LC-MS in the field of toxicology, such as "general unknown" screening procedures and mass spectral libraries using LC-atmospheric pressure ionization (API)-MS or MS-MS, presenting the different solutions proposed to overcome the naturally low fragmentation power of API sources. Finally, the opportunities afforded by the most recent or proposed instrument designs are addressed.