The ultimate purpose of signal transduction is to transmit extracellular or cytoplasmic stimuli to the nuclear interior to elicit a cellular response, mediated primarily through changes in gene expression. The evolution of the nuclear envelope and the consequent compartmentalization of the genome, which is a defining feature of eukaryotes, introduced a physical barrier to the free access of genes. Initially regarded as nothing more than this, a physical barrier with selective permeability, recent findings have transformed our view of the nuclear envelope and its diverse roles in various aspects of cell biology and human diseases, much of which is only beginning to be understood. The realization that mutations in genes encoding nuclear envelope proteins cause a diverse array of tissue-selective diseases often referred to as "laminopathies" has provided new insight into structural and regulatory functions of the nuclear envelope. Genetic mutations causing abnormalities in the nuclear envelope can lead to dysregulated signaling that underlies pathogenesis of these diseases. The emerging picture indicates that the nuclear envelope is a node that fine-tunes signaling output and as such it may play a role in the biology of cancer.