The retinal pigment epithelium (RPE) is a monolayer of pigmented cells localized between the photoreceptors and the blood vessels of the choroid. Being the most important interaction partner with the photoreceptors in visual function, any change in RPE function leads to photoreceptor degeneration. The structural integrity and function of the tissue complex “photoreceptor-RPE-choroid” is dependent on close spatial interaction of those cells. This is achieved on one hand by the interphotoreceptor matrix which forms a matrix between RPE and photoreceptors. On the other hand, Bruch’s membrane forms another interface between RPE and choroid. These interfaces enable free exchange of nutrients, oxygen, and bioactive molecules such as growth factors or cytokines between the cells and layers of the photoreceptor-RPE-choroid complex. The adhesion between the layers is ensured by the elimination of extracellular fluid by the RPE towards the choroid as well as by the maintenance of the protein composition of the extracellular matrix. Pathogenesis of retinal pigment epithelial detachment (PED), however, is not yet fully clarifed; different concepts try to explain the development of PED under different circumstances. The most widely accepted concept is that RPE detachment can be caused by a reduced fluid flow through an ageing Bruch’s membrane or by a passive inflow of water caused by changes in osmolarity of the extracellular matrix, e.g., in age-related macular degeneration or degenerative PED. Idiopathic PED (e.g., in central serous chorioretinopathy) is thought to result from choroidal dysfunction and increased permeability of choroidal vessels, possibly due to overactivation of mineralocorticoid receptors in the choroidal endothelial cells. Local inflammation or ischemia can also lead to hyperpermeability of choroidal vessels and thereby to inflammatory/ischemic PED.