Nuclear architecture, a function of both chromatin and nucleoskeleton structure, is known to change with stem cell differentiation and differs between various somatic cell types. These changes in nuclear architecture are associated with the regulation of gene expression and genome function in a cell-type specific manner. Biophysical stimuli are known effectors of differentiation and also elicit stimuli-specific changes in nuclear architecture. This occurs via the process of mechanotransduction whereby extracellular mechanical forces activate several well characterized signaling cascades of cytoplasmic origin, and potentially some recently elucidated signaling cascades originating in the nucleus. Recent work has demonstrated changes in nuclear mechanics both with pluripotency state in embryonic stem cells, and with differentiation progression in adult mesenchymal stem cells. This review explores the interplay between cytoplasmic and nuclear mechanosensitivity, highlighting a role for the nucleus as a rheostat in tuning the cellular mechano-response.