Urine drug testing is frequently used in clinical, employment, educational, and legal settings and misinterpretation of test results can result in significant adverse consequences for the individual who is being tested. Advances in drug testing technology combined with a rise in the number of novel misused substances present challenges to clinicians to appropriately interpret urine drug test results. Authors searched PubMed and Google Scholar to identify published literature written in English between 1946 and 2016, using urine drug test, screen, false-positive, false-negative, abuse, and individual drugs of abuse as key words. Cited references were also used to identify the relevant literature. In this report, we review technical information related to detection methods of urine drug tests that are commonly used and provide an overview of false-positive/false-negative data for commonly misused substances in the following categories: cannabinoids, central nervous system (CNS) depressants, CNS stimulants, hallucinogens, designer drugs, and herbal drugs of abuse. We also present brief discussions of alcohol and tricyclic antidepressants as related to urine drug tests, for completeness. The goal of this review was to provide a useful tool for clinicians when interpreting urine drug test results and making appropriate clinical decisions on the basis of the information presented.