An accurate analysis is required to address various issues concerning the food safety. Many risk factors, such as agricultural chemical residues, residual veterinary drugs, mycotoxins, food additives, and carcinogens produced during food processing may be present in foodstuffs. High-performance liquid chromatograph-tandem mass spectrometry (LC-MS/MS) is an analytical system advanced in terms of sensitivity, selectivity, and flexibility. The system has been widely applied to food analysis. Food contains a wide variety of nutritional components, which may cause interference with food analyses. Then, sample preparation to remove such interference and an appropriate choice of an analytical technique is required. Even with LC-MS/MS, the analytical reliability may be reduced by matrix effects, due to interference from food components. In this review, we summarize issues on using LC-MS/MS to achieve good analyses for the food safety and discuss how to address it. The topic especially focuses on matrix effects.