Much attention has focused on the role of co-stimulation in dictating tolerance versus immunity to internalized antigens, with the assumption that the presentation of antigen-derived peptides by MHC molecules occurs constitutively. Here, I highlight our new appreciation for the regulated presentation of phagocytosed antigens by MHC class II molecules as a direct result of controlling phagosome maturation by Toll-like receptors. I discuss how the mode of antigen delivery into dendritic cells coupled with the right type of signal transduction pathway can impact greatly not only the co-stimulatory context in which the antigen is presented to naive T cells (signal 2) but MHC-II presentation of the antigen and formation of the T-cell receptor ligand (signal 1) itself.