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Diabetic macular edema (DME) is the most common cause of vision loss in diabetic patients. Multiple therapeutic options are currently available for these patients, including laser photocoagulation; intravitreal injections of anti-vascular endothelial growth factor (VEGF) drugs or steroids; or pars plana vitrectomy for tractional DME. The initial treatment for DME is well-defined and widely accepted, with anti-VEGF as first-line option. Nevertheless, between 30 and 40% of patients show partial response or no response whatsoever. There is no consensus on the number of injections needed in order to classify a patient as a non-responder or sub-optimal responder, nor on the definition of the latter. In this study, these concepts are analysed as well as the different therapeutic alternatives at hand, with special interest on the switch between different anti-VEGF and/or steroids. These analyses are performed from an anatomical and functional point of view as well as from an economic, cost-effectiveness perspective. Recent evidence suggests that an early switch to dexamethasone implant in eyes that did not respond adequately to anti-VEGF therapy after 3 injections provides better functional outcomes while alleviating the heavy economic burden of this disease.