Nuclear factor of activated T cells (NFAT) is a transcription factor that translocates from cytosol to nucleus following dephosphorylation by the Ca(2+)/calmodulin dependent protein phosphatase calcineurin (CN). In nervous tissue, aberrant CN signaling is increasingly linked to a variety of pathologic features associated with Alzheimer's disease (AD), including synaptic dysfunction, glial activation, and neuronal death. Consistent with this linkage, our recent work on postmortem human hippocampal tissue discovered increased nuclear accumulation of select NFAT isoforms at different stages of AD. Some of these changes occurred at the early stages of the disease process and/or paralleled diminishing cognitive status. In addition, inhibition of astrocytic NFAT activity in primary cultures of neurons and glia dampened glutamate levels and alleviated neuronal death in response to pathogenic amyloid-β peptides. In this article, we discuss our recent findings and expand upon the possible isoform specific contributions of NFATs to the progression of AD. We also consider the possible benefits of using NFAT inhibitors to treat AD and other neurodegenerative disorders, as well.