Epigenetic modification of chromatin, including histone methylation and acetylation, plays critical roles in eukaryotic cells and has a significant impact on chromatin structure/accessibility, gene regulation and, susceptibility to aging, neurodegenerative disease, cancer, and other age-related diseases. This article reviews the current advances on TIP60/KAT5, a major histone acetyltransferase with diverse functions in eukaryotes, with emphasis on its regulation of autophagy, proteasome-dependent protein turnover, RNA transcription, DNA repair, circadian rhythms, learning and memory, and other neurological functions implicated in aging and neurodegeneration. Moreover, the promising therapeutic potential of TIP60 is discussed to target Alzheimer's disease and other neurological diseases.