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• The astrocytic Na+, K + ATPase plays a key role in the main homeostatic functions of astrocytes. • Loss-of-function mutations in the α2 Na+, K + ATPase cause a rare form of migraine with aura (FHM2). • FHM2 knock-in mice with 50 % reduced expression of α2 Na+, K + ATPase show increased susceptibility to cortical spreading depression and hypersensitivity to a migraine trigger. • Upregulation of the astrocytic α2 Na+, K + ATPase in mouse models of ALS and AD promotes neuroinflammation and contributes to progressive neurodegeneration. The Na+, K + ATPases play a fundamental role in the homeostatic functions of astrocytes. After a brief historic prologue and discussion of the subunit composition and localization of the astrocytic Na+, K + ATPases, the review focuses on the role of the astrocytic Na+, K + pumps in extracellular K + and glutamate homeostasis, intracellular Na+ and Ca2+ homeostasis and signaling, regulation of synaptic transmission and neurometabolic coupling between astrocytes and neurons. Loss-of-function mutations in the gene encoding the astrocytic α2 Na+, K + ATPase cause a rare monogenic form of migraine with aura (familial hemiplegic migraine type 2). On the other hand, the α2 Na+, K + ATPase is upregulated in spinal cord and brain samples from amyotrophic lateral sclerosis and Alzheimer disease patients, respectively. In the last part, the review focuses on i) the migraine relevant phenotypes shown by familial hemiplegic migraine type 2 knock-in mice with 50 % reduced expression of the astrocytic α2 Na+, K + ATPase and the insights into the pathophysiology of migraine obtained from these genetic mouse models, and ii) the evidence that upregulation of the astrocytic α2 Na+, K + ATPase in mouse models of amyotrophic lateral sclerosis and Alzheimer disease promotes neuroinflammation and contributes to progressive neurodegeneration. [Display omitted] [ABSTRACT FROM AUTHOR]