In the present study, we have investigated the role and molecular mechanism of H19 lncRNA in chemoresistance using doxorubicin resistance in breast cancer cells as a model system, and demonstrated for the first time that H19 lncRNA is a key mediator of chemoresistance in breast cancer cells, functioning at the far upstream of the H19-CUL4A-MDR1 molecular pathway. This evidence concerns the gene H19 and breast cancer.