Developments over the last 15 years have led to widespread acceptance and commercialization of two liquid chromatography-mass spectrometry (LC-MS) interfaces: thermospray (TSP) and particle beam (PB). Very few LC-MS methods have been developed and formally adopted, however, by the U.S. Environmental Protection Agency (EPA). This article addresses the difficulties encountered with current LC-MS instrumentation in validating the methods and discusses some of the results of three interlaboratory EPA studies, including a thermospray-LC-MS (TSP-LC-MS) study for chlorinated herbicides, a TSP-LC-MS study for carbamate pesticides, and a particle beam-LC-MS (PB-LC-MS) study for benzidines. Differences in features among the various LC-MS interfaces made it impractical to impose strict guidelines to the participants in conducting these analyses. Consequently, difficulties were encountered in analyzing the data; nonetheless, interesting and useful data, as outlined in this article, were obtained.