The keys to the illegal manufacture of methamphetamine (meth) are pseudoephedrine and ephedrine, which are List I chemicals commonly used as decongestants in over-the-counter cough, cold, and allergy medicines. The diversion of over-the-counter pseudoephedrine-containing products is one of the major contributing factors to the meth situation in the United States. Typically, a meth cook extracts pseudoephedrine by placing the over-the-counter product in a solution of water, alcohol, or another solvent for several hours, then converting it to high-quality meth by using a variety of common household products and equipment. For drug enforcement agencies to get to the root of this production chain, they must be able to identify the exact sources and manufacturing pathways of meth seized from clandestine laboratories. Crucial to this effort is the accurate separation and identification of pseudoephedrine from illegal drug mixtures, particularly from the meth group compounds, including amphetamine, methamphetamine, and 3,4-methylenedioxy-N-methamphetamine (3,4-MDMA). This article describes how ultra-high-performance liquid chromatography (UHPLC)/mass spectrometry (MS) can be used to perform high-throughput separation, identification, and quantitation of pseudoephedrine. The ppb-level (ng/mL) sensitivity and accuracy of this method not only facilitates the identification and quantification of pseudoephedrine and/or other components in illicit drug sample; it also is an efficient tool for determining the source and manufacturing pathway of drugs seized in the illicit market. 2 tables, 3 figures, and 7 references