To ensure compliance with food safety regulations, monitoring programs and reliable analytical methods to detect relevant chemical pollutants in food and the environment are key instruments. Pesticides are an important part of pest management in agriculture to sustain and increase crop yields and control post-harvest decay, while pesticide residues in food may pose a risk to human health. Thus, the levels of pesticide residues in food must be controlled and should align with Maximum Residue Levels regulations to ensure food safety. Food safety monitoring programs and analytical methods for pesticide residues and metabolites are well developed. Future developments to ensure food safety must include the increased awareness and improved regulatory framework to meet the challenges with natural toxins, emerging contaminants, novel biopesticides, and antimicrobial resistance in food and the environment. The reality of a complex mixture of pollutants, natural toxins, and their metabolites potentially occurring in food and the environment implies the necessity to consider combined effects of chemicals in risk assessment. Here, we present challenges, monitoring efforts, and future perspectives for chemical food safety focused on the importance of current developments in high-resolution mass spectrometry (HRMS) technologies to meet the needs in food safety and environmental monitoring.