Ample evidence suggests that oxidative stress and other external stressors contribute to retinal and retinal pigment epithelium (RPE) pathology, as implicated in diseases like age-related macular degeneration. Therefore the understanding of cellular protection against these insults is of therapeutic importance. We adapted two approaches for studying the mechanisms of macular and retinal degeneration. In one, the contribution and significance of these pathologic processes was investigated by use of cultured human and mouse RPE. In the in vivo counterpart studies, we assessed the importance of α-crystallins in the retina (and RPE) in models using knockout mice and cobalt chloride injections. In addition to α-crystallins, we looked at other oxidative stress protectants of the cell and examined the redox regulation and antioxidant functions mediated by hepatocyte growth factor (HGF). These studies have greatly contributed to the elucidation of the pathways involved in retinal dysfunction and examine the protective mechanisms offered by hepatocyte growth factor and α-crystallins in oxidative-stressed retina.