This review focuses on recent investigation of a unique group of autoantibodies that enter cells, transit though the cytoplasm, prior to their final destination either in the nucleus or at other sites within the cell. Cellular and nuclear entry is determined by the antigen binding region of the antibodies. Differences in antigenic specificity appear to influence both the ultimate cellular destination of the antibodies and the perturbations of cell function resulting from their interaction with intracellular ligands. Further investigation of these autoantibodies has the potential to provide both insights into the intracellular behavior of large proteins, and more efficient mechanisms of delivery of agents to specific sites within the cell.