Excessive inflammation is considered as a critical factor in many human diseases, including cancer, obesity, type II diabetes, cardiovascular diseases, neurodegenerative diseases and aging. Compounds derived from botanic sources, such as phenolic compounds, have shown anti-inflammatory activity in vitro and in vivo. Recent data suggest that polyphenols can work as modifiers of signal transduction pathways to elicit their beneficial effects. These natural compounds express anti-inflammatory activity by modulation of pro-inflammatory gene expression such as cyclooxygenase, lipoxygenase, nitric oxide synthases and several pivotal cytokines, mainly by acting through nuclear factor-kappa B and mitogen-activated protein kinase signalling. This review will discuss recent data on the control of inflammatory signalling exerted by some dietary polyphenols contained in Mediterranean diet. A clear understanding of the molecular mechanisms of action of phenolic compounds is crucial in the valuation of these potent molecules as potential prophylactic and therapeutic agents.