Lamin-associated polypeptides (LAPs) comprise inner nuclear membrane proteins tightly associated with the peripheral lamin scaffold as well as proteins forming stable complexes with lamins in the nucleoplasm. The involvement of LAPs in a wide range of human diseases may be linked to an equally bewildering range of their functions, including sterol reduction, histone modification, transcriptional repression, and Smad- and β-catenin signaling. Many LAPs are likely to be at the center of large multi-protein complexes, components of which may dictate their functions, and a few LAPs have defined enzymatic activities. Here we discuss the definition of LAPs, review their many binding partners, elaborate their functions in nuclear architecture, chromatin organization, gene expression and signaling, and describe what is currently known about their links to human disease.