 Neurodegenerative disorders, such as Alzheimer's disease, are a global public health burden with poorly understood etiology. Neuroinflammation and oxidative stress, OS, are hallmarks of neurodegeneration contributing to disease progression. Protein aggregation and neuronal damage result in the activation of disease-associated microglia, DAM, by a damage-associated molecular patterns, DAMPs. DAM facilitate persistent inflammation and reactive oxygen species, ROS, generation. However, the molecular mechanisms linking DAM activation and OS have not been well-defined, thus targeting these cells for clinical benefit has not been possible. In microglia, ROS are generated primarily by NADPH oxidase 2, NOX2, and activation of NOX2 in DAM is associated with DAM signaling, inflammation, and amyloid plaque deposition, especially in the cerebrovascular. Additionally, ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation, thus intracellular ROS signaling may underlie excessive inflammation and OS. Targeting key kinases in the inflammatory response could cease inflammation and promote tissue repair. Expression of antioxidant proteins in microglia, such as NADPH dehydrogenase 1 and Q01, is promoted by transcription factor NRF2, which functions to control inflammation and limit OS. Lipid droplet accumulating microglia, LDAM, may also represent a double-edged sword in neurodegenerative disease by sequestering peroxideized lipids in nonpathological aging but becoming dysregulated and pro-inflammatory in disease. We suggest that future studies should focus on targeted manipulation of NOX in the microglia to understand the molecular mechanisms driving inflammatory-related NOX activation. Finally, we discuss recent evidence that therapeutic target identification should be unbiased and founded on relevant pathophysiological assays to facilitate the discovery of translatable antioxidant and anti-inflammatory therapeutics. This article was authored by Dominic S. A. Simpson and Peter L. Oliver. We're article.tv, links in the description below.