TGN38 is a protein of unknown function located in the trans-Golgi network (TGN) of mammalian cells. Its intracellular distribution is maintained by it being continuously retrieved from the plasma membrane. In this paper we show that when cells are treated with agents such as chloroquine which neutralize acidic organelles, the movement of TGN38 along the endocytic pathway is blocked. The same effect is observed with a second TGN protein, the protease furin. We show that the cytoplasmic tail of furin is sufficient to confer a chloroquine-sensitive TGN localization on a heterologous protein. These results imply that the internal pH of endosomes affects sorting processes mediated by signals in the cytoplasmic portion of proteins and have implications for the role of acidification in endosomal function.