Oligodendrocytes have a complex cytoarchitecture and are characterized by an elaborate network of microtubules. They provide the tracks for organelle trafficking and the intracellular translocation of myelin-specific gene products. The integrity of the cytoskeleton is an essential determinant of the function and survival of oligodendrocytes. Microtubule growth and stability are regulated by microtubule-associated proteins. Oligodendrocytes contain a number of microtubule-associated proteins, including the tau proteins, which are developmentally regulated and especially prominent in the branching points of the cellular processes. Process outgrowth is regulated by the interaction of Fyn kinase with the cytoskeleton and by microtubule-severing proteins, such as stathmin. Alterations or disruption of the cytoskeleton and abundant abnormal aggregates of cytoskeletal proteins often accompany neurodegenerative diseases, and inclusion bodies, resembling protein aggregates found in neurons, are prominent in oligodendroglial lesions in white matter pathology. This review emphasizes the role of the cytoskeleton, particularly of microtubules and their associated proteins, in oligodendrocytes during developmental processes. Furthermore, recent data on protein aggregate formation in oligodendroglial cells, which might occur during aging and disease processes, are summarized.