The significance of polyphenols, with emphasis to flavonoids, in the responses of Mediterranean plants to unfavorable environments, is discussed based on their ability to serve multiple functions in plant-environment interactions. Plants challenged against multiple stressors, as usually occurs in the Mediterranean basin, make a great investment in the biosynthesis of carbon-based-secondary-compounds, i.e., defense compounds sensu lato. Polyphenols are probably the most versatile secondary metabolites, thus allowing plants to respond promptly to unpredictable stress agents of different origin. Each individual species indeed displays a rich arsenal of polyphenol structures, which have different inter- and intra-cellular distribution. This review article is centered on the functions of polyphenols, particularly flavonoids as UV-screening, antioxidant and developmental regulators, and the relative significance of these roles in the acclimation/adaptation of plants to severe constrains of the Mediterranean climate. Here we suggest that flavonoids serve major roles as antioxidants rather than UV-screening pigments in Mediterranean plants challenged against an excess of sunlight irradiance. Furthermore, we discuss about the potential of flavonoids, particularly antioxidant flavones and flavonols, to regulate the development of organs and the whole plant. This ability may have great value for the ecology of plants inhabiting unfavorable Mediterranean environments, but this matter needs further investigation.