The polarized phenotype of the retinal pigment epithelium is crucial for the outer retina-blood barrier and support of photoreceptors and underlying choroid, and its disruption plays a central role in degenerative retinopathies. Although the mechanisms of polarization remain mostly unknown, they are fundamental for homeostasis of the outer retina. Recent research is revealing a growing picture of interconnected tissues in the outer retina, with the retinal pigment epithelium at the center. This review discusses how elements of epithelial polarity relate to emerging apical interactions with the neural retina, basolateral cross-talk with the underlying Bruch’s membrane and choriocapillaris, and tight junction biology. An integrated view of outer retina physiology is likely to provide insights into the pathogenesis of blinding diseases.