There is now compelling evidence for the aging-related breakdown of cytoskeletal support in neurons. Similarly affected are the principal components of the intracellular microtubule system, the transport units involved in active shuttle of organelles and molecules in an antero- and retrograde manner, and the proteins stabilizing the cytoskeleton and providing trophic support. Here, we review the basic organization of the cytoskeleton, and describe its elements and their interactions. We then critically assess the role of these cytoskeletal proteins in physiological aging and aging-related malfunction. Our focus is on the microtubule-associated protein tau, for which comprehensive investigations suggest a critical role in neurodegenerative diseases, for instance tauopathies. These diseases frequently lead to cognitive decline and are often paralleled by reductions in cholinergic neurotransmission. We propose this reduction to be due to destabilization of the cytoskeleton and protein transport mechanisms in these neurons. Therefore, maintenance of the neuronal cytoskeleton during aging may prevent or delay neurodegeneration as well as cognitive decline during physiological aging.