The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. Laminopathies are diseases caused by mutations in genes encoding protein components of the lamina and these other nuclear envelope substructures. Mutations in the single gene encoding lamin A and C, which are expressed in most differentiated somatic cells, cause diseases affecting striated muscle, adipose tissue, peripheral nerve, and multiple systems with features of accelerated aging. Mutations in genes encoding other nuclear envelope proteins also cause an array of diseases that selectively affect different tissues or organs. In some instances, the molecular and cellular consequences of laminopathy-causing mutations are known. However, even when these are understood, mechanisms explaining specific tissue or organ pathology remain enigmatic. Current mechanistic hypotheses focus on how alterations in the nuclear envelope may affect gene expression, including via the regulation of signaling pathways, or cellular mechanics, including responses to mechanical stress.