Laser photocoagulation is a photothermal process in which heat is produced by the absorption of laser energy by targeted tissues. The purpose of the treatment is to induce thermal therapeutic damage, which causes biological reactions and ultimately beneficial effects. The current endpoint of laser photocoagulation of the chorioretina is an ophthalmoscopically visible retinal whitening. Retinal blanching is the sign that the retina itself has been thermally damaged and results in a number of undesired adverse events. The mechanisms underpinning the efficacy of laser photocoagulation are still poorly understood. However, recent hypotheses postulate that full thickness retinal damage may not be needed to obtain beneficial therapeutic effectiveness. Preliminary studies with laser photocoagulation on animals demonstrated the ability to create therapeutic lesions confined around the Retinal Pigment Epithelium (RPE) cells without causing apparent damage to the overlying retina. The laser impacts were not visible by slit lamp biomicroscopy at the time of laser delivery. Recent experiments showed that the beneficial effect of retinal photocoagulation is mediated by factors derived from the RPE. Non Ophthalmoscopically Visible Endpoint Photocoagulation (NOVEP) protocols might allow treatments that confine minimal therapeutic damage around the cells of the RPE and minimize the damage to the neurosensory retina.