In the mouse, cross-presentation is an exclusive property of the CD8α+ subset of dendritic cells (DC) but the basis for this selectivity remains unclear. Here we report that splenic CD8α+ DC are much superior to other DC subsets in internalizing dying cells in vitro. In contrast, CD8α+, CD8α– CD4+ and CD8α– CD4– DC subsets phagocytose bacteria or latex beads to a similar extent. Although CD8α+ DC are better than CD4+ DC at presenting ovalbumin (OVA)-loaded splenocytes to naïve OT-I T lymphocytes, CD4+ DC are better at presenting OVA-expressing Escherichia coli to the same T cells. In both cases, presentation is abrogated by lactacystin. These results show that both splenic CD8α+ and CD8α– DC can present exogenous antigens on major histocompatibility complex (MHC) class I via a proteasome-dependent pathway and suggest that the specialized cross-presenting function of CD8α+ DC is a result of their ability to endocytose dying cells rather than a unique pathway for handling endosomal contents.