Recent evidence revealed that presentation of soluble antigens is governed by the endocytosis mechanisms that determine the intracellular routing of the endocytosed antigens. Soluble antigens intended for classical exogenous MHC-II-restricted presentation are internalized into lysosomes. Soluble antigens destined for crosspresentation are taken up by distinct endocytosis mechanisms and are conveyed into stable early endosomes. Particulate antigens enter phagosomes, in which both MHC-I-restricted and MHC-II-restricted presentation is initiated. In this review, we discuss the mechanistical differences in presentation of soluble and particulate antigen, the correlation of various endocytic receptors with antigen routing and presentation, the differential expression of these receptors in antigen-presenting cell subsets with respect to their ability to crosspresent, and implications on the molecular mechanisms controlling cross-presentation.