Major histocompatibility complex (MHC) molecules present peptide antigens to T lymphocytes and initiate immune responses. The peptides loaded onto MHC class I or MHC class II molecules can be derived from cytosolic proteins, both self and foreign. A variety of cellular processes, including endocytosis, vesicle trafficking, and autophagy, play critical roles in presentation of these antigens. We discuss the role of autophagy, a major intracellular degradation system that delivers cytoplasmic constituents to lysosomes in both MHC class I and II-restricted antigen presentation. We propose the new term “Type 2 cross-presentation” (CP2) to define the autophagy-dependent processes leading to MHC II-restricted presentation of intracellular antigens by professional antigen presenting cells. A better understanding of Type 2 cross-presentation may guide future efforts to control the immune system through autophagy manipulation.