Many medications that are administered systemically for nonocular conditions may evoke ocular toxicological complications. Therefore, the eye is routinely investigated histopathologically in preclinical in vivo toxicity studies. The retinal pigment epithelium is a likely target for systemically administered compounds, since the underlying choroid is highly vascularized. The specialized pigment epithelium has numerous functions that all maintain the integrity and function of photoreceptors. Consequently, toxic effects on the pigment epithelium will eventually affect the neural retina. The potential of pigment epithelial cells to respond to toxic injury is limited, but a standardized terminology to describe its morphological changes does not exist in the scientific literature. Detailed morphologic analysis, however, might allow early detection of retinotoxicity and may provide evidence on the underlying pathomechanism. We here review toxic effects on the pigment epithelium focusing in particular on the morphology of toxic cell injury. Morphological changes comprise hypertrophy, intracytoplasmic accumulation of cellular components, loss of cell polarity, degeneration, metaplasia, and formation of subretinal membranes. Some of these changes are reversible whereas others are permanent, leading to impaired function of the pigment epithelium and eventually to photoreceptor loss and retinal atrophy.