More than 7000 synthetic compounds known as per- and poly-fluoroalkyl substances (PFAS) are applied to food packaging and other materials to provide fat, fire, and/or water resistance properties. These compounds have exceptional environmental stability and persistence due to the strong C-F chemical bond, earning them the moniker “forever chemicals”. Emission of PFAS from industrial waste leads to water, air, and soil contamination. Due to this ubiquitous nature, combined with the fact that PFAS in humans are known to have carcinogenic and reprotoxic effects and to cause vaccine resistance and depression of the immunity system, PFAS may constitute a major threat to human health. For this reason, the attention of the scientific community and of control bodies is increasing and as a consequence legislation and the scientific literature on PFAS are constantly evolving. This review aims to provide a comprehensive overview of the state of the art about current legislation addressing PFAS; targeted and screening method for identification, detection and quantification of PFAS; toxicity of PFAS; and contamination of environmental and food matrices and from food contact matrices. A comprehensive review of the latest scientific research and recent developments in the legislation of PFAS will provide insights into the current understanding of PFAS and its health implications. Moreover, it will serve as a valuable reference for further studies related to PFAS and could help in informing future policy decisions.