The dogmatic and at one time prevalent concept that intact antibody molecules were not able to enter into viable cells has now been modified due to the availability of a large amount of experimental findings and clinical observations that indicate otherwise. Penetration of mature autoantibodies into living cells might participate in the pathogenesis of diverse autoimmune diseases, through inducing apoptosis of healthy tissues and cells, but also by contributing to the breakdown of self-tolerance through presentation of self-antigens to the immune system. Conversely, the penetration of naturally occurring autoantibodies into immature lymphoid cells might have a physiological role in the edition of the immune repertoire in healthy individuals. Increasing interest is being paid to the potential immunotherapeutic role of penetrating antibodies as tools to deliver drugs, isotopes or genes into cells.