During evolution, plants developed a complex set of morphological, biochemical and molecular, preformed and inducible defense mechanisms that allowed them to live in stressful conditions. In addition, the ability of plants to synthesize organic compounds (primary and secondary metabolites and plant hormones) has ensure success in colonizing challenging environments. With the practice of intensive monoculture, aiming to feed an increasingly numerous population, the incidence of plant viruses has increased almost in the same proportion. Thus, aggressive control practices to the environment and human health such as the use of pesticides began to be recommended in an uncontrolled way, which has encouraged the search for a more sustainable agriculture. Therefore, understanding the mechanisms used by viroses to interfere with metabolism in compatible and incompatible interactions, as well as those used by plants to overcome or not the infection, is fundamental and can help to clarify important points in plant-virus interactions, enabling the recommendation and use of ecologically friendly crop management. In this review, the molecular aspects of plant-virus interactions, the metabolic changes induced by the viruses, the use of natural products to control plant viruses and the application of these compounds in sustainable agriculture will be addressed.