Diabetic retinopathy (DR) and diabetic macular edema (DME) are leading causes of vision loss globally. This is a comprehensive review focused on both medical and surgical management strategies for DR and DME. This review highlights the epidemiology of DR and DME, with a particular emphasis on the Asia-Pacific region, urban-rural disparities, ethnic variations, and grading methodologies. We examine various risk factors for DR, including glycemic control, hypertension, hyperlipidemia, obesity, chronic kidney disease, sex, myopia, pregnancy, and cataract surgery. Furthermore, we explore potential biomarkers in serum, proteomics, metabolomics, vitreous, microRNA, and genetics that may aid in the detection and management of DR. In addition to medical management, we review the evidence supporting systemic and ocular treatments for DR/DME, including anti-vascular endothelial growth factor (anti-VEGF) agents, anti-inflammatory agents, biosimilars, and integrin inhibitors. Despite advancements in treatment options such as pan-retinal photocoagulation and anti-VEGF agents, a subset of cases still progresses, necessitating vitrectomy. Challenging diabetic vitrectomies pose difficulties due to complex fibrovascular proliferations, incomplete posterior vitreous detachment, and fragile, ischemic retinas, making membrane dissection risky and potentially damaging to the retina. In this review, we address the question of challenging diabetic vitrectomies, providing insights and strategies to minimize complications. Additionally, we briefly explore newer modalities such as 3-dimensional vitrectomy and intra-operative optical coherence tomography as potential tools in diabetic vitrectomy. In conclusion, this review provides a comprehensive overview of both medical and surgical management options for DR and DME. It underscores the importance of a multidisciplinary approach, tailored to the needs of each patient, to optimize visual outcomes and improve the quality of life for those affected by these sight-threatening conditions.