Pluripotent stem cells (PSCs) are capable of differentiating into all three germ layers and trophoblasts, whereas tissue-specific adult stem cells have a more limited lineage potency. Although the importance of the cytoskeletal architecture and cytomechanical properties in adult stem cell differentiation have been widely appreciated, how they contribute to mechanotransduction in PSCs is less well understood. Here, we discuss recent insights into the interplay of cellular architecture, cell mechanics and the pluripotent states of PSCs. Notably, the distinctive cytomechanical and morphodynamic profiles of PSCs are accompanied by a number of unique molecular mechanisms. The extent to which such mechanobiological signatures are intertwined with pluripotency regulation remains an open question that may have important implications in developmental morphogenesis and regenerative medicine.