The major challenge in vaccine development a gainst various disease-causing organisms is to use defined antigen to stimulate appropriate immune responses that lead to resistance. The use of peptide-based vaccine is gaining greater attention asits flexibility in the incorporation of multiple defined and different epitopes into a single construct for eliciting d esirable arms of the immune system. It is generally safer than the use of live a ttenuated vaccine while it is relative ease of manufacture than subunit vaccine. However, development of peptide-based vaccine faces significant challenges. This approach has limited ability to elicit immune responses in a genetically dive rse outbred population due to the Major Histocompatibility Complexes (MHC) polym orphism. For the same reason, peptide immunizations often elicit inadequate cyto toxic T lymphocyte (CTL) and antibody (Ab) responses due to the lack of appropri ate helper Tlymphocyte (HTL) activity. Another possible disadvantage of using linear peptide construct is that, for eliciting appropriate antibody responses, s urface immunoglobulin (Ig) receptor clustering is needed in order to activate th e resting B cells. Problems caused by MHC polymorphism may be circumvented by the use of promiscuous T-cell epitopes. Promiscuous T-cell epitopes from the mea sles virus F protein (amino acid [aa] 288 to 302) and a murine defined T-helper cell epitope (V1E8, aa 191-209) that bind to multiple MHC molecules have bee n identified and have been used in highly immunogenic constructs to overcome hap lotype-restricted immune responses. Synthetic non-natural Pan DR Epitope (PADR E) which have degenerate binding capacity to several common HLA-DR can enhance immunogenicity of short-peptide immunogen, both in terms of absolute titers and quality of antibody responses. Besides, a number of so called "promiscuous" T -cell epitopes from Influenza virus hemagglutinin (HA), Plasmodium falciparum pre-erythrocytic stage antigens and mycobacterial proteins have been reporte d to be universally immunogenic. For promiscuous binding to several isotypic and allotypic forms of MHC class Ⅱ molecules, these peptides should display overla pping MHC-binding motifs or should use anchors that are conserved among ligands and should lack allele-specific anchor residues that would prevent binding wit h the other class Ⅱ molecules. Understanding the biophysical basis for both the promiscuity and the specificity of peptide recognition by MHC Ⅱ molecules will provide a molecular rationale for strategies to overcome genetic restriction in the context of vaccine design.