Endogenous reactive intermediates such as photoexcited states of tissue chromophores, reactive oxygen species (ROS), reactive carbonyl species (RCS), and transition metal ions are mediators of tissue damage involved in initiation and progression of human pathologies including tumorigenesis, atherosclerosis, diabetes, and neurodegenerative disease. A large body of evidence now suggests that B6 vitamers antagonize the harmful activity of endogenous reactive intermediates fulfilling a very different role than that established as a cofactor for numerous enzymes. In this chapter, the structural basis of vitamin B6 activity as a potent antioxidant, metal chelator, carbonyl scavenger, and photosensitizer is presented and the physiological relevance is discussed.