The mechanical properties of the interphase nucleus have important implications for cellular function and can reflect changes in nuclear envelope structure and/or chromatin organization. Mutations in the nuclear envelope proteins lamin A and C cause several human diseases, such as Emery-Dreifuss muscular dystrophy, and dramatic changes in nuclear stiffness have been reported in cells from lamin A/C-deficient mice. We have developed a cellular strain technique to measure nuclear stiffness in intact, adherent cells and have applied this experimental method to fibroblasts from mouse models of Emery-Dreifuss muscular dystrophy and to skin fibroblasts from laminopathy patients and healthy control subjects. The experimental protocol is based on measuring induced nuclear deformations in cells plated on a flexible silicone substrate; the nuclear stiffness can subsequently be inferred from the ratio of induced nuclear strain to the applied membrane strain. These experiments reveal that lamins A and C are important determinants of nuclear stiffness and that lamin mutations associated with muscular dystrophies and other laminopathies often result in disturbed nuclear stiffness that could contribute to the tissue-specific disease phenotypes.