Caspase-2, a multifunctional member of the cysteine-aspartic protease (caspase) family, has emerged as a compelling therapeutic target across multiple neurodegenerative diseases. Unlike current strategies that aim to halt disease progression by clearing pathological aggregates (e.g., amyloid-β or hyperphosphorylated tau), inhibition of caspase-2 offers a means of functional restoration – specifically, the rapid reversal of synaptic deficits and associated cognitive impairment. This chapter reviews the physiological and pathological roles of caspase-2, with a focus on its cleavage of the neuronal scaffold protein tau at aspartate-314 (Asp314), a mechanistic axis implicated in Alzheimer’s disease, Lewy body dementia, frontotemporal dementia, and other diseases. We also summarize recent translational progress in developing caspase-2 inhibitors, with a special emphasis on peptide-based structures.