The loading of class II MHC molecules with antigenic peptides is largely confined to the endocytic vesicles of specialized antigen-presenting cells (APCs), such as B cells, macrophages and dendritic cells. At first glance, the pathway utilized by each of these professional APCs to generate class II–peptide complexes on their surface appears to be indistinguishable. All three types of APC rely on the chaperone Ii for correct class II assembly and transport to the endocytic pathway, they all depend on the action of specific cysteine proteases to remove Ii from the class II–Ii complex, and they all utilize the class II-like molecule DM to facilitate peptide loading. A closer look, however, reveals subtle yet important differences in the class II maturation pathway between each of these APCs, which befit the unique roles these individual cells play in eliciting CD4⁺ T-cell responses.