•The response of astrocytes to injury is a major determinant of the outcome after stroke.•In the acute phase, reactive astrocytes are neuroprotective.•In the post-acute and chronic phase, astrocytes act as both positive and negative regulators of neural plasticity.•Modulation of astrocyte function at this later stage appears as an attractive strategy to improve functional outcome.•Astrocyte intermediate filament (nanofilament) proteins may represent the right target for this objective, and the complement system may be at least one of the suitable bullets to hit it. Stroke is an acute insult to the central nervous system (CNS) that triggers a sequence of responses in the acute, subacute as well as later stages, with prominent involvement of astrocytes. Astrocyte activation and reactive gliosis in the acute stage of stroke limit the tissue damage and contribute to the restoration of homeostasis. Astrocytes also control many aspects of neural plasticity that is the basis for functional recovery. Here, we discuss the concept of intermediate filaments (nanofilaments) and the complement system as two handles on the astrocyte responses to injury that both present attractive opportunities for novel treatment strategies modulating astrocyte functions and reactive gliosis.