Lake Ecosystems have experienced a significant loss of their ecological value due to various human activities. It has been recognized that the continued alteration of freshwater biodiversity is not sustainable, and also, it has been realized that less modified freshwater ecosystems provide significant economic and social benefits to society. In Greece, changes in land and water management, driven by the increase in agricultural production and the urban expansion, have created multiple stressors on lentic ecosystems which cannot be ignored any longer. The objective of the present study is to describe some of these stressors, and to identify their impacts on Greek lakes. We collected an extensive dataset from twelve natural lakes using several metrics, also suggested by the Water Framework Directive (WFD), along with specific ecohydrological characteristics. Our results demonstrate severe impact on water quality and quantity with consequence to the lake’s functions, and extended eutrophication in almost all lakes. The Greek lakes have been subjected to various hydromorphological alterations, which affect their metabolism, while the aforementioned effects are further maximized due to particularities of the Mediterranean climate. The set up of good management practices through multipurpose management plans are also discussed.