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ABSTRACT The ability of cells to sense and respond to mechanical signals is essential for many biological processes that form the basis of cell identity, tissue development and maintenance. This process, known as mechanotransduction, involves crucial feedback between mechanical force and biochemical signals, including epigenomic modifications that establish transcriptional programs. These programs, in turn, reinforce the mechanical properties of the cell and its ability to withstand mechanical perturbation. The nucleus has long been hypothesized to play a key role in mechanotransduction due to its direct exposure to forces transmitted through the cytoskeleton, its role in receiving cytoplasmic signals and its central function in gene regulation. However, parsing out the specific contributions of the nucleus from those of the cell surface and cytoplasm in mechanotransduction remains a substantial challenge. In this Review, we examine the latest evidence on how the nucleus regulates mechanotransduction, both via the nuclear envelope (NE) and through epigenetic and transcriptional machinery elements within the nuclear interior. We also explore the role of nuclear mechanotransduction in establishing a mechanical memory, characterized by a mechanical, epigenetic and transcriptomic cell state that persists after mechanical stimuli cease. Finally, we discuss current challenges in the field of nuclear mechanotransduction and present technological advances that are poised to overcome them.