In Drosophila, the tumor suppressor Scribble is localized at the septate junctions of epithelial cells. Its mammalian homologue, hScrib, is a basolateral protein likely associated to proteins of the cell–cell junctions. We report the direct interaction between hScrib and ZO‐2, a junction‐associated protein. This interaction relies on two PDZ domains of hScrib and on the C‐terminal motif of ZO‐2. Both proteins localise at cell–cell junctions of epithelial cells. A point mutation in the LRR of hScrib delocalises the protein from the plasma membrane and abrogates the interaction with ZO‐2 but not with βPIX. Tyrosine phosphorylation of hScrib does not impair the interaction with ZO‐2. We show a direct link between two junctional proteins that are down‐regulated during cancer progression.