Per- and poly-fluoroalkyl substances are a group of synthetic aliphatic compounds containing one or more perfluoroalkyl moieties (CnF2n + 1-). Due to their unique surface-active properties and high chemical and thermal stability, they are used in various consumer products such as cosmetics, food packaging, furnishings, and textiles. Their use dates back to the 1940s. Despite their peculiar performances, recent scientific works investigate their sustainability and safety deriving from environmental ubiquity, persistence and bioaccumulation. Indeed, these chemicals are not metabolized in animals and are eliminated mainly through the kidneys, with a low excretion capacity in the case of humans. Many studies conducted worldwide have reported significant serum levels of per- and poly-fluoroalkyl substances in most of the general population, associating them with several health conditions, including hepatoxicity, dyslipidaemia, and endocrine and immunotoxicity outcomes. Besides, new sources of emissions due to degradation phenomena are continuously identified. Consequently, long-chain per- and poly-fluoroalkyl substances have triggered supervising actions and restrictions that fostered research about possible alternatives. This article aims to screen current European scientific investigations conducted to evaluate the impact of these chemicals on the environment and human health, focusing on food packaging and textile production. Due to the paper’s length limitation, not all the scientific literature is described because of the need to leave space to discuss possible substitutes. Relevant studies are reported about implementing sustainability and safety/hazard assessment for per- and poly-fluoroalkyl substances. Eventually, the need to develop new and specific analysis methods is discussed.