We are interested in the mechanism and therapeutic strategy for the alteration of retinal neuronal integrity in diabetic retinopathy (DR) and other hypoxic retinal diseases. In this article, we will discuss our work in exploring the relationship between vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) in the maintenance of major retinal supporting cells, Müller cell (MC), and in investigating the potential role and mechanisms of BDNF-mediated MC viability through its signaling cascade under diabetic and hypoxic conditions. While our data suggest that BDNF is a positive regulator of MC viability through the classical survival and proliferation pathways under diabetic/hypoxic conditions, the biological significance of BDNF-mediated MC viability in diabetes/hypoxia remains unclear, which is a major challenge in designing BDNF-mediated neuroprotective strategy for DR and hypoxic retinal disorders.