In the last decades, significant changes have been taking place regarding the pathogenesis of diabetic retinopathy (DR) and the complex mechanisms that eventually lead to the various manifestations of the disease, including diabetic macular edema (DME). DR was first considered a pure microvascular disease, due to the evident capillary structural changes (microaneurysms), fluid extravasation, and lipid exudation. With the advent of fundus fluorescein angiography, the concept of ischemia and the correlation between peripheral nonperfusion and neovascularization has been introduced, which was eventually followed by the advent of new therapeutic strategies, such as peripheral photocoagulation. Nowadays, thanks to more advanced imaging techniques, namely optical coherence tomography (OCT), OCT angiography, and wide-field imaging (imaging up to 200° of the retina in a single shot), it became clear that other elements participate in the occurrence of DR and DME, including inflammation and neurodegeneration. In the future, integration of standard investigations with new diagnostic devices would allow the prompt recognition of DR even before clinical signs of the disease are ophthalmoscopically evident, and the development of personalized treatment for both retinopathy and DME will be available.