Lycopene, a natural carotenoid found in tomato, has been reported to possess various health benefits, such as cardiovascular and cancer preventive properties. However, the experimental basis for such health benefits is not fully understood. One of the possible mechanisms for its protective activities is by down-regulation of the inflammatory response. That includes the inhibition of pivotal pro-inflammatory mediators, such as the reduction of reactive oxygen species, the inhibition of synthesis and release of pro-inflammatory cytokines, changes in the expression of cyclooxygenase and lipoxygenase, modifications of eicosanoid synthesis, and modulation of signal transduction pathways, including that of the inducible nitric oxide synthase via its inhibitory effects on Nuclear Factor-kB (NF-kB), Activated protein-1 (AP-1) and mitogen-activated protein kinase (MAPK) signaling. Recent data suggest that lycopene also exhibits anti-inflammatory activity through induction of programmed cell death in activated immune cells. This review will discuss recent data on the control of inflammatory signaling exerted by tomato lycopene in isolated cells, in animal models and in clinical trials, focusing on the dose of the carotenoid and the biological environment in which it acts. A clear understanding of the molecular mechanisms of action of lycopene is crucial in the valuation of this molecule as a potential preventive and therapeutic agent.