The microtubule-associated protein tau is a predominantly axonal neuronal protein and involved in the pathogenesis of Alzheimer’s disease (AD). Tau is a target of multiple protein kinases and gets progressively hyper-phosphorylated at multiple sites, contributing to the formation of neurofibrillary tangles and cognitive decline in AD. My team’s work builds on the discovery of that a member of the p38 mitogen-activated protein (MAP) kinase family targets tau at the post-synapse, thereby inhibiting toxic signals downstream of tau. This site-specific phosphorylation confers an unprecedented neuroprotective function of tau. We extend this work now to therapeutic concepts as well as to a broad approach to how site-specific and hyper-phosphorylation of tau are connected in health and disease.