The activation of MHC class II-restricted helper T cells is paramount to ad
aptive immune responses. Vaccine development could therefore benefit from i
mproved ways of targeting antigens into MHC class II molecules. In recent y
ears, the natural pathways of MHC class II antigen presentation have been e
xploited to achieve this goal. First, antigenic proteins and peptides have
been modified to facilitate receptor-mediated uptake by professional antige
n-presenting cells. Second, DNA constructs containing specific targeting se
quences have been used to direct endogenously synthesized antigens to the M
HC class II compartments. Both strategies proved to be highly effective. We
review these data and describe how this knowledge is currently applied to
the design of vaccines that activate helper T cells in vivo.