Positive drug tests for amphetamines are frequently challenged with “innocent” explanations. Common defenses include the use of over-the-counter (OTC) decongestants (e.g., pseudoephedrine, ephedrine, phenylpropanolamine), nasal inhalers containing l-methamphetamine (Vicks® inhaler), herbal supplements for weight loss (ma huang/ephedra, bitter orange), or allegedly contaminated dietary supplements. Modern toxicology has advanced significantly in distinguishing true illicit amphetamine/methamphetamine use from such claims. Improved immunoassays, confirmatory chromatography (GC/MS and LC–MS/MS), chiral analysis of enantiomers, and high-resolution mass spectrometry (HRMS) now enable clear differentiation between false-positive immunoassay screens and true positive results. Emerging evidence highlights numerous prescription and nonprescription substances that either cross-react with amphetamine screening assays or are metabolized into amphetamines. This chapter updates the scientific and clinical knowledge since the original edition, providing toxicologists, MROs, and forensic scientists with current strategies to defend or refute positive amphetamine results, including comprehensive tables of interfering substances and metabolite-producing drugs.