The classical macrophage is one of the most important cells involved in presenting antigen to helper T cells, because of its ability to regulate its expression of Ia molecules and to encounter and process particulate and soluble antigens. We have summarized in this report studies examining the handling by macrophages of two different antigens, the bacteria Listeria monocytogenes and the protein hen egg white lysozyme (HEL). The purpose was to identify potential sources of immunogenic peptides. Presentation of Listeria required an intracellular processing stage sensitive to lysosomotropic drugs. The Listeria required internalization and processing, after which immunogenic molecules were recognized by T cells on the macrophage surface. Metabolic studies showed that Listeria‐derived peptides were released by macrophages that had phagocytosized the bacteria. The release of these peptides was a temperature‐dependent process, unaffected by inhibiting lysosomal catabolism by treatment with chloroquine. Listeria‐derived peptides were also detected on the surface of the macrophage. These peptides behaved like integral membrane proteins, some of which persisted for at least 24 hr at the macrophage surface. When tested for immunogenicity, the released peptides were very weakly immunogenic. The membrane‐associated peptides alone could not stimulate Listeria‐specific T cells, but could be reprocessed by additional macrophages and subsequently stimulate the T cells. A defined antigen system using HEL‐specific T‐cell hybridomas was used to examine the processing of HEL. Presentation of HEL required a choloroquine‐sensitive intracellular processing stage. In examining two T‐cell hybridomas, a differential requirement for antigen processing was determined. The immunogenicity of released HEL from HEL‐pulsed macrophages was also tested, and no “processed” antigen was detected capable of directly stimulating T cells; however, native HEL was released from the macrophage and could be processed and presented by other macrophages.