Intermediate filaments (IFs) are cytoskeletal polymers whose protein constituents are encoded by a large family of differentially expressed genes. Owing in part to their properties and intracellular organization, IFs provide crucial structural support in the cytoplasm and nucleus, the perturbation of which causes cell and tissue fragility and accounts for a large number of genetic diseases in humans. A number of additional roles, nonmechanical in nature, have been recently uncovered for IF proteins. These include the regulation of key signaling pathways that control cell survival, cell growth, and vectorial processes including protein targeting in polarized cellular settings. As this discovery process continues to unfold, a rationale for the large size of this family and the context-dependent regulation of its members is finally emerging.