Fruits are an important part of a healthy diet. They provide essential vitamins and minerals, and their consumption is associated with a reduced risk of heart disease and certain cancers. These important plant products can, however, be expensive to purchase, may be of disappointing quality and often have a short shelf life. A major challenge for crop improvement in fleshy fruit species is the enhancement of their health-promoting attributes while improving quality and reducing postharvest waste. To achieve these aims, a sound mechanistic understanding of the processes involved in fruit development and ripening is needed. In recent years, substantial insights have been made into the mechanistic basis of ethylene biosynthesis, perception and signalling and the identity of master regulators of ripening that operate upstream of, or in concert with a regulatory pathway mediated by this plant hormone. The role of other plant hormones in the ripening process has, however, remained elusive, and the links between regulators and downstream processes are still poorly understood. In this review, we focus on tomato as a model for fleshy fruit and provide an overview of the molecular circuits known to be involved in ripening, especially those controlling pigment accumulation and texture changes. We then discuss how this information can be used to understand ripening in other fleshy fruit-bearing species. Recent developments in comparative genomics and systems biology approaches are discussed. The potential role of epigenetic changes in generating useful variation is highlighted along with opportunities for enhancing the level of metabolites that have a beneficial effect on human health.