As the mechanism of BSEP targeting concerning bile physiology and cholestatic diseases have been more elucidated, the finding of the novel BSEP-interacting protein CHMP5 and the unraveling of the mechanism mediating the polarized trafficking of BSEP via ESCRT machinery may provide clues for developing new therapeutic approaches for BSEP-associated cholestasis. Here, ABCB11 is linked to cholestasis.