Among microorganisms found in food, fungi stand out because they are adaptable and competitive in a large range of water activities, temperatures, pHs, humidities and substrate types. Besides sporulating, some species are toxigenic and produce toxic metabolites, mycotoxins, under adverse biotic and abiotic variables. Microorganisms are inactivated along the food chain, but mycotoxins have stable structures and remain in ready-to-eat food. The most prevalent mycotoxins in food, which are aflatoxins, fumonisins, ochratoxin A, patulin, tenuazonic acid, trichothecenes and zearalenone, have maximum tolerable limits (MTLs) defined as ppb and ppt by official organizations. The chronic and acute toxicities of mycotoxins and their stability are different in a chemical family. This critical review aims to discuss promising scientific research that successfully mitigated levels of mycotoxins and focus the results of our research group on this issue. It highlights the application of natural antifungal compounds, combinations of management, processing parameters and emergent technologies, and their role in reducing the levels and bioaccessibility. Despite good crop management and processing practices, total decontamination is almost impossible. Experimental evidence has shown that exposure to mycotoxins may be mitigated. However, multidisciplinary efforts need to be made to improve the applicability of successful techniques in the food supply chain to avoid mycotoxins’ impact on global food insecurity.