The blood-ocular barrier system is formed by 2 main barriers: the blood-aqueous barrier and the blood-retinal barrier (BRB). The BRB is particularly tight and restrictive and is a physiologic barrier that regulates ion, protein, and water flux into and out of the retina. The BRB consists of inner and outer components, the inner BRB being formed of tight junctions between retinal capillary endothelial cells and the outer BRB of tight junctions between retinal pigment epithelial cells. The BRB is essential to maintaining the eye as a privileged site and is essential for normal visual function. Methods of clinical evaluation of the BRB are reviewed and new directions using optical coherence tomography are presented. Alterations of the BRB play a crucial role in the development of retinal diseases. The 2 most frequent and relevant retinal diseases, diabetic retinopathy and age-related macular degeneration (AMD), are directly associated with alterations of the BRB. Diabetic retinopathy is initiated by an alteration of the inner BRB and neovascular AMD is a result of an alteration of the outer BRB. Macular edema is a direct result of alterations of the BRB.