The general principles for safety and nutritional evaluation of foods and feed and potential health risks associated with hazardous compounds have been developed by FAO and WHO and further elaborated in the EU funded project Safe Foods, where specific attention was given to a coherent scientific analysis of health and environmental risk-benefits and impacts on economics, social and ethical aspects. Nevertheless, the crucial role that sampling has in foods/feed safety assessment has never been explicitly recognized. High quality sampling should always be applied to ensure the use of adequate and representative samples as test materials for all the steps of food/feed safety assessment: hazard identification, toxicological and nutritional characterization of identified hazards, as well as estimation of quantitative and reliable exposure levels of foods/feed or related compounds of concern for humans and animals. The different types of substances under study which are present in food/feed matrices and commodities, raw or semi-processed, pose both general and specific challenges to the development of appropriate sampling strategies and analytical detection methods. Although it is well recognized that both sampling and analytical errors affect the reliability of any final risk estimation, traditionally much more attention has been devoted to the development and improvement of analytical methods, as compared to the development of appropriate sampling plans. But the reality is that analytical results are of low or no value, no matter the quality of the method used, if the sampling process is not representative of the entire field-to-aliquot pathway.