The retinal pigment epithelium (RPE) is a close, interactive partner to the photoreceptors as well as an interface with the endothelium of the choroid and thus with the body's circulatory system. To fulfill these roles, the RPE communicates with neighboring tissue by secretion of a large variety of factors and is able to react to secreted factors via a plethora of transmembrane receptors. Clinically relevant local pharmacological effects are caused by anti-VEGF-A treatment in choroidal neovascularization or by carboanhydrase inhibitors reducing fluid accumulation in the macula. Being exposed to the bloodstream, the RPE reacts to systemic disease, such as diabetes or hypertension, but also to systemic pharmacological intervention, for example to hypotensive drugs acting on the renin-angiotensin-system. Sustained pharmacological treatments, in particular, cause side effects at the RPE with consequences for both RPE function and photoreceptor survival. Among these are systemic inhibition of angiotensin-converting enzyme, insulin treatment in diabetes and anti-VEGF-A therapy. Given the special anatomical and functional relationships of the RPE, pharmacological intervention targeting either the eye or the body systemically should take potential alteration of RPE and subsequently photoreceptor function into account.