The nature of these drug metabolites, especially phase II metabolites, gives LC-MS a unique advantage for analysis of drugs and their metabolites using LC-MS, MS/MS and MSn applications for identification, structural determination, and mapping PK/PD interactions during ADME30. (GC-MS), liquid chromatography MS (LC-MS), inductively coupled plasma ionization MS (ICP-MS), tandem mass spectrometry (MS/MS and MSn) have emerged as powerful tools used in toxicology laboratories. This review will focus on these hyphenated MS technologies and their applications for toxicology. Key words: Environmental toxicology, clinical toxicology, forensic toxicology, mass spectrometry technologies == INTRODUCTION == Toxicology can be thought of as the study of poisons, how poisonous encounters occur, how individuals respond to these encounters, and how to develop strategies for the clinical management of toxic exposures1. Poisons can be broadly defined as biologically active substances causing toxic effects in living systems. In essence, any biologically active molecule capable of altering normal physiology within a living system becomes a poison upon accumulation to quantities sufficient for a toxic effect1. For this reason, even therapeutic remedies can become poisons and toxic effects depend not only on the dose, but also on the overall pharmacokinetic and pharmacodynamic SirReal2 effects2. Since we are constantly surrounded by various chemicals, exposure can occur at home, work, or from the environment. The sheer complexity of possible poisons requires the use of sophisticated analytical tools and techniques to evaluate toxic exposures3-6. Toxic evaluations usually begin with qualitative or quantitative assessment in order to identify and/or quantify a toxic substance that could account for observed toxic syndromes (toxidromes) which are characteristic of different classes of poisons7. In addition , identification of the source for toxic exposures is equally important. However , the overall role of laboratory testing is to identify and confirm the presence of a suspected poison and also to provide prognostic information when test results are able to predict clinical outcomes and/or help guide patient management. In toxicology, the general analytical scheme for assessment of poisons in various matrices involves; 1) extraction, 2) purification 3) detection and 4) quantification (Scheme 1, A)8. The rise of modern analytical tools used by toxicology laboratories seems to have coincided with the chemical/industrial revolution (roughly 1850s to 1950s). A time which saw development of new liquid-liquid and solid-phase extraction methods along with qualitative or quantitative methods of detecting poisons based on their physical characteristics8, 9. By the early twentieth century, chromatographic techniques using differential migration processes for separation of target molecules were developed by Mikhail Tsvet9and with the first versions of modern separation techniques such as liquid chromatography SirReal2 (LC) and gas-liquid chromatography (GLC or simply gas chromatography, GC) became routine in both analytical and preparative applications by mid-20th century1, 10, 11. At this time, labs also started to see the development of the first versions of modern mass spectrometers being used primarily for analysis of relatively pure materials11-12. == p35 Scheme 1 . == The analytical process for toxic compound evaluation in toxicology As MS, GC and LC technologies continued to advance in the second half of the 20th century, the more sophisticated methods used in modern toxicology laboratories started to emerge as amalgamations of separation and detection modes, creating new powerful analytical applications. These SirReal2 included; high pressure liquid chromatography (HPLC), GC-MS, LC-MS, MS/MS and MSn. These new technologies SirReal2 were initially used by research laboratories and later adopted into clinical laboratories11, 13. To date, many of the modern analytical applications such as GC-MS and LC-MS still incorporate the same analytical scheme used by the earliest toxicology laboratories. But they are more stream-lined by combining multiple steps in the process with potential for automation (Scheme 1, B). This review will highlight current MS applications for Toxicology. == Mass spectrometry == Mass spectrometry is a quantitative technique which determines the mass-to-charge (m/z) ratio. In general, a mass spectrometer can be divided into four main components (Scheme 1, B): 1) a sample inlet, 2) an ion source, 3) a mass analyzer, and 4) a detector. The sample inlet is where the sample enters the instrument before reaching the ion source. Ion sources are generally distinguished based on their underlining ionization technique11, 12. The ionization technique used will determine the type of sample (e. g solid, liquid, vs gaseous samples) that can be analyzed in a given instrument and therefore also the type of chromatographic separation technique that should be coupled to the MS. Furthermore, the efficiency of sample.