Demand for exotic goods, such as wine and oranges, continues to grow in the western world. However, agricultural regulations can vary significantly from region to region. Regulatory bodies, such as the United States Food and Drug Association (US FDA), routinely screen all imported goods to ensure they meet the domestic limits of tolerance. Detection of low concentrations of pesticides within complex matrices, such as orange juice and wine, is a complex process that requires a high level of sensitivity. This article details how a newly developed “dilute-and-shoot” sample preparation method for LC–MS–MS multi-residue monitoring (MRM) pesticide screening can be performed to overcome matrix effects.