Since the dawn of time, grapevine trunk diseases (GTDs) have been responsible for a sizeable decline in vineyards worldwide. Results from recent studies have found that the mycobiome composition of the woody tissues in symptomatic plants and close to leaves manifesting the ‘tiger stripes’ symptoms of esca, as well as in leaf-symptomatic canes, is highly similar to that of plants not exhibiting any symptoms. The role of fungi as primary pathogens causing GTDs within the microbiome of grapevine remains to clarify. Among the new hypotheses attempting to explain the emergence of GTDs, hydraulic failure of the plant’s vascular system due to vessel obstruction by fungi, pruning wounds and/or climatic stress are the most likely. Studies in plant physiology are only just beginning to identify the co-factors that may promote wood diseases and the degrading role of involved fungi. This chapter proposes a perspective on the problem of vine decline, integrating these different parameters, including phytotoxins.