In injury and disease, microglia and astrocytes - two major non-neuronal cell types in the central nervous system (CNS) - undergo morphological, transcriptional, and functional changes, which can underlie pathogenesis and dysfunction of the CNS. Microglia, the brain's tissue resident parenchymal macrophages, are described as becoming “activated” as they deftly change their production of different inflammatory mediators, alter the surveillance behavior of their cellular protrusions, and differentially influence the function of astrocytes. For their part, astrocytes – the most abundant glial cell type – are said to become “reactive”, which implies (perhaps inappropriately) causality for the changes astrocytes undergo. Reactive astrocytes variably undergo process hypertrophy, decrease their normal homeostatic functions such as facilitating synapse formation, and in some cases act to form a tissue scar in response to insult. But what do these terms “activation” and “reactivity” mean, anyway? And how do these changed microglia and astrocytes contribute to neurodegenerative disease (ND)? Here, we describe our current understanding of the role of activated and reactive microglia and astrocytes in ND, as well as our current understanding about what these states are and might mean. We survey the earliest description of these cells by histopathologists, their transcriptomic identities, and finally our mechanistic understanding of their functions in ND.