Potent MHC class II antigenic peptide vaccines are created by covalently linking the N-terminus of a MHC class II epitope through a polymethylene bridge to the C-terminus of the Ii-Key segment of the Ii protein. Such hybrids enhance potency of presentation in vitro of the MHC class II epitope about 200 times relative to the epitope-only peptide. In vivo, as measured by IFN-gamma ELISPOT assays, the helper T cell response to vaccination is enhanced up to 8 times. The design of such hybrid vaccine peptides comes from insight into the mechanism of action of the Ii-Key motif within the Ii protein, in regulating antigenic peptide binding into the antigenic peptide binding groove of MHC class II molecules. Here we present the logic and experimental history of the development of these vaccine peptides, with particular attention to the hypothesized mechanism of action. Methods for the design and testing of these peptides are presented. Experience in developing peptide vaccines for immunotherapy of cancer is reviewed, focusing on the clinical potential of Ii-Key/MHC class II epitope hybrids.