Abstract: A transdermal system for sustained delivery of high molecular weight hydrophilic drugs, especially peptide-, polypeptide- or protein-drugs, and methods of use thereof, are provided. The system includes an apparatus that generates micro-channels in the skin of a subject in combination with a transdermal patch comprising at least one drug reservoir layer comprising a polymeric matrix and a therapeutic or immunogenic peptide, polypeptide, or protein. The system provides sustained delivery of therapeutic or immunogenic agents, thereby achieving sustained therapeutic blood concentrations of these agents.