The recent discovery of fusion of endoplasmic reticulum membrane with nascent phagosomes suggests that this peripheral compartment in macrophages and dendritic cells may serve as an organelle optimized for major histocompatibility complex (MHC) class I–restricted cross-presentation of exogenous antigens. The process allows intersection of the endosomal system with the endoplasmic reticulum, the classical site of MHC class I peptide loading, and may reconcile the seemingly conflicting evidence indicating both of these sites are crucial in cross-presentation. Here we discuss the potential mechanisms involved in loading exogenous antigens onto MHC class I molecules and the implications of this new evidence for the in vivo function of dendritic cells.