The effect of light in combination with a chemical or a natural compound is termed photosensitization, and is known to have multiple cellular effects. Among them, modulation of gene expression is one of the most important, because it directly influences cell adaptation to novel environmental conditions. In previous years, the cis- and trans-acting genetic elements responsible for gene regulation by radiation and photosensitization, in particular, have been well characterized. The molecular mechanisms involved in the cell response revealed that an important control occurs at the transcriptional level and is coordinated by various transcription factors. The extracellular or intracellular changes mediated by photosensitization are detected by several signal transduction networks, allowing cells to mount an appropriated response in term of gene regulation. Mitogen-activated protein kinases (MAPK) and phosphatidylinositol 3-kinases (PI3-K) are among the most thoroughly studied of signal transduction systems and have been shown to participate in a diverse array of cellular programs. In this review, we will show how these cascades can be activated by photosensitization. A third signal type of transduction machinery, which has been shown to be activated by photosensitization, is the one leading to the activation of the Rel/NF-kappaB family of transcription factors. This family includes many members, most of which can form DNA-binding homo- or heterodimers. We will show that molecular mechanisms leading to NF-kappaB activation by photosensitization are initiated by oxidative damage. While the exact nature of the transduction intermediates is still unknown, NF-kappaB activation by radiation followed different pathways from those used by pro-inflammatory cytokines.