Commercial fruit trees are usually formed by the combination of a rootstock and a scion to broaden the adaptability of scion cultivars to soil and climatic conditions, facilitate agricultural management, and/or increase productivity. In the different cultivated species of the genus Prunus, rootstocks having a wide range of uses are scarce, because of rootstock/ scion graft incompatibilities that prevent the establishment of a strong and lasting functional union. Graft incompatibility is a problem in cherry, almond, and apricot than in peach or plum. In general, closely related cultivars and species tend to be compatible, but taxonomically distant plants often manifest incompatibility. This review will focus on the knowledge currently available on the metabolic response during the formation and establishment of the stock/scion graft union in order to help the effort for identify future metabolic markers to be used in breeding programs. The physiological, metabolic and molecular mechanisms that cause incompatibility remain unclear and several hypotheses have been proposed to explain it, mostly based on herbaceous species. Few studies are available to explain incompatibility in woody plants. Various phenolic compounds are known to affect cell division, development and differentiation at the graft union. Flavonol (catechins and proanthocyanidins) concentrations increase shortly after grafting and, as a result of the stress induced during the healing response, vacuolar membrane disruption occurs resulting in the escape of phenols from the vacuole into the cytoplasmic matrix, causing dysfunctions in the growth of certain tissues (xylem and phloem), interference with the synthesis of lignin or inducing hormonal imbalances. All these abnormalities result in mechanical weakening of the union, which may manifest during the first year after grafting (translocated incompatibility) or may appear several years later (localized incompatibility), leading to major economic losses. More research is needed to fully understand the mechanism of graft incompatibility, particularly in woody plants. This knowledge is essential to develop molecular markers useful in rootstock breeding programs.