Eukaryotic cells display considerable morphological plasticity linked to their abilities to carry out a myriad of complex functions. Structural rearrangements associated with cellular activities, from yeast mitosis to cell migration in the mammalian central nervous system, often involve relocation of the cell nucleus. Recent studies have provided insight into how nuclear components can be mechanically coupled to the cytoskeleton, providing a more complete understanding of the role of nuclear positioning in both health and disease.