Compared to "live" vaccines the immunogenicity of "split" vaccines is notably poor, because exogeneous antigens (Ag) insufficiently access the MHC class I processing pathway needed for cross-presentation. Here we review our evidence that targeting ligands of endosomally expressed Toll-like Receptors (TLRs), together with exogeneous Ag to endosomes of dendritic cells (DCs) conveys immunogenicity to Ag similar in magnitude as "live" vaccines that produce Ag. We explored the consequences of enforced endocytosis of "Ag plus TLR ligands" either by crosslinking Ag and CpG-Oligonucleotides (CpG-Ag conjugates) or by co-encapsulating Ag plus endosomally expressed TLR ligands in biodegradable microspheres (MP). While both approaches equally well yielded in effective cross-priming of MHC class I restricted CD8 T effector cells, our data recommend MP as a generally applicable endosomal delivery device to vaccinate for protective and therapeutic CD4 and CD8 T cell immunity. Furthermore, our data suggest that functional inactivation of Foxp3(+) regulatory T cells further enhances the immunogenicity of "split vaccines".