The neurosensory retina is a highly specialized sense organ that is subjected to constant exposure of systemic toxins, oxidative stress and focused light rays. Important advances have been made in recent decades in unravelling a myriad of defence mechanisms against such insults and consequently in improving the understanding of the principles underlying various drug- and light-induced disease processes. To defend against circulating toxins, the retina possesses a specialized blood-retinal barrier (BRB) that tightly regulates the transport of substances across the functional boundaries of the retina at the retinal capillaries and the retinal pigmented epithelium. An endogenous cytochrome p450 system is strategically located within the retina to neutralize agents that can diffuse through the BRB. The biooxidation effect of light is prevented by a wide array of unique antioxidant mechanisms in the retina. Nonetheless, pathological processes may evolve when these different lines of defence are overwhelmed by various xenobiotics, environmental agents such as cigarette smoke and excessive light exposure, particularly of short wavelength high frequency blue light and ultraviolet light. Latest research using transgenic models has revealed novel apoptotic pathways implicated in acute phototoxicity, in particular blue light damage, and provides important clues for further understanding the risks of high-frequency light exposure to human retinopathy. This review article summarizes the basic scientific principles of these different defence mechanisms and discuss the implications in pathophysiology and treatment.