The brain is composed of many different cells that are tightly interconnected during health and disease. Astrocytes are integral to the normal function of the healthy brain, providing nutrients to neurons and microglia. During Alzheimer’s disease (AD), one type of astrocyte switches from a support role to a pathological one: slowing neuron communication, decreasing connections between neurons and becoming less efficient at removing waste products—all important for a healthy and normally functioning brain. In extreme cases, these astrocytes actively kill neurons. We have localized these toxic reactive astrocytes to regions of dead and dying neurons in both animal models of AD and in human patients. Importantly, we find this neurotoxic function does not depend on the underlying genetics of individual patients. This makes targeting neurotoxic reactive astrocytes an exciting novel avenue for the development of new therapies. Our exciting novel methods to maintain positive components of inflammation and target only the production and release of a specific astrocyte neurotoxin provides unrivaled control over this complex system. We continue to investigate the role of astrocyte-derived neurotoxins in initiation and progression of AD. Results from these studies will give us a better understanding of basic astrocyte biology, and will provide new targets for development of future therapies.