Mesotrione (2-[4-(methylsulfonyl)-2-nitrobenzoyl]-cylohexane-1,3-dione) is an herbicide brought to the market 15 years ago and commonly used on maize cultures. This review summarizes the results obtained from worldwide scientific studies on its efficiency, effects, and fate in environment, in order to bring first overall conclusions about its safety of use. The comprehensive review of the available scientific literature reveals that mesotrione applied as recommended ensures the desired effects on sensitive crops, mainly in post-emergence application, while exhibiting favorable toxicological, and environmental profile. According to the studies realized so far, mesotrione presents no significant risks to humans and other non-target organisms or to the environment. Its degradation by soil microorganisms is fast, ensuring a low possibility to retrieve mesotrione in ground water. Its terminal residues in soil, maize, grain, and maize straw are below the limit of quantification. All these results suggest that mesotrione applied as directed ensures the respect of current environmental standards and food safety. Future prospects should focus on its associated pesticides when applied in mixtures on field, and on the detection, quantification, and risk assessment of its transformation products in order to exclude any toxicological synergistic effects.