Macroautophagy is a catabolic process for the lysosomal turnover of cell organelles and protein aggregates. Lysosomal degradation products are displayed by major histocompatibility class II molecules to CD4(+) T cells in the steady state for tolerance induction and during infections to mount adaptive immune responses. It has recently been shown that macroautophagy substrates can also give rise to MHC class II ligands. We review here the breadth of antigens that may utilize this pathway and the possible implications of this alternate route to MHC class II antigen presentation for immunity and tolerance. Based on this discussion, it is apparent that the regulation of macroautophagy may be beneficial in various disease settings in order to enhance adaptive immune responses or to reduce autoimmunity.