Diabetic retinopathy (DR) is a major cause of visual impairment worldwide. Visual reduction in patients with DR is usually related to diabetic macular edema (DME). Today, the intravitreal injection of anti-vascular endothelial growth factors (VEGF) is replacing macular laser photocoagulation as the standard treatment for DME; however, in some patients, incomplete responses to the anti-VEGF injection, defined as refractory DME, may occur. Currently, the sequence of using one treatment option and the timing to switch from one agent to another is not fully understood, and the data from clinical trials on the appropriate approach to manage refractory DME is insufficient. In the current study, a review was conducted to evaluate therapeutic options for the management of refractory DME.