A huge natural variation exists between individuals within a given plant species. Most of the responses of growth-related traits to different environmental scenarios are genotype dependent. Hence, natural variation in plants provides an interesting and valuable source of genetic diversity to study plant responses to environmental factors. The identification of genes that underlie phenotypic variation has an enormous practical implication by providing a means to improve crop yield and quality. The approach based on natural variation aims to use naturally occurring differences to improve our knowledge about complex physiological responses of plants to their environment, including nutrition efficiency. An overview of different approaches currently used in plant research aimed at dissecting complex quantitative traits is presented here, with a special focus on those related to Nutrient Use Efficiency, to explain strategies based on QTL mapping in segregating populations and association mapping in wild populations. Some case studies regarding each of the investigative strategies described are detailed.