Studies of osteopontin (OPN)-dependent regulation of immune responses have focused on the cytokine activities of the secreted form of this protein. Recent evidence has revealed that an intracellular form of OPN expressed by dendritic cells regulates the expression of pro-inflammatory cytokines and the differentiation of T helper (T_H)-cell lineages. In this Opinion article, we discuss the properties of both OPN isoforms and their respective contributions to the immune response. We propose that cell-type-specific expression of secreted and intracellular OPN regulates the development of distinct effector T_H cells, including that of T_H1 and T_H17 cells.