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Disease progression is accompanied by changes in the brain microenvironment, but how these shifts in biochemical, biophysical, and cellular properties contribute to repair outcomes or continued degeneration is largely unknown. Tissue engineering approaches can be used to develop in vitro models to understand how the brain microenvironment contributes to pathophysiological processes linked to neurological disorders and may also offer constructs that promote healing and regeneration in vivo. In this Perspective, we summarize features of the brain microenvironment in normal and pathophysiological states and highlight strategies to mimic this environment to model disease, investigate neural stem cell biology, and promote regenerative healing. 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