Leaf size and shape define the photosynthetic capability of a plant and have a significant impact on important agronomic traits, such as yield, quality, disease resistance and stress responses. Cultivated varieties of many plant species show remarkable variations in leaf morphology. Such variation usually exhibits a continuous phenotypic distribution and is controlled by the interaction of multiple genes known as quantitative trait loci (QTL). Here, we review several studies that evaluate natural variations in the leaf morphologies of crop species, as well as in the model plant Arabidopsis thaliana. The use of high-throughput, genome-wide approaches such as transcriptomics and metabolomics is helping to identify the nucleotide polymorphism(s) responsible for the phenotypic differences attributed to some of these QTL.