The aldehydes derived from lipid oxidation are highly active electrophilic compounds including saturated aldehydes, dialdehydes, olefin aldehydes and hydroxyl aldehydes. The active groups like carbonyls, C=C bond, and hydroxyl groups make them prone to participate in chemical reactions with protein, phospholipids, which can further affect food properties. In addition, aldehydes can attack the nucleic acids and thiol group of endogenous antioxidants, result in oxidative stress and biological damage of cells, which usually serve as the direct trigger of various diseases. However, their structure-activity relationship has not received enough attention. Therefore, to provide a comprehensive understanding of reactive aldehydes on food safety and human health, the formation mechanism of aldehydes, attributable fundamental thermal processing, analytical methods, and toxicological effects based on the structure-activity relationship, have been reviewed and discussed. It was indicated that aldehydes generation exerted significant specificity of fatty acids substrate. Significant structure-activity relationships for the toxicological effects of aldehydes could be observed. Effective, accurate and eco-friendly detection techniques should be established based on the inherent advantages and limitations for food quality preservation and safety assurance.