Abstract: With the increase of life expectancy and population growth, neurodegenerative diseases have risen too and are projected to be a major health public concern by 2050. Neurodegenerative diseases are characterized by the progressive decline of cognitive function leading to the subsequent loss of autonomy. Although the underlying causes of neurodegeneration are not well understood, aging is the main risk factor. Interestingly, more than 17 neurodegenerative diseases present Tau protein dysregulation as a hallmark of degeneration. Tau protein, which can be hyperphosphorylated, hyperacetylated, cleaved, alternative spliced, mutated, and form neurofibrillary tangles (NFT’s), has multiple cellular functions that could potentially be compromised and lead to neurodegeneration. Nevertheless, Tau’s biology remains largely unknown to this day despite its wide interest in the scientific community. In this perspective, we highlight some of the layers of regulation that make Tau’s universe so elusive and challenging for its apprehension and the ramifications of such complexity with emphasis at the nucleus.