Provided are methods and means to obtain improved gene silencing of target nucleic acids whereby at least two inhibitory RNA molecules are provided which are targeted to the same nucleic acid, but which are processed into short interfering RNA molecules through different processing pathways. Also provided are methods and means to obtain improved gene silencing of target nucleic acids whereby at least two inhibitory RNA molecules are provided which are targeted to different nucleic acids, but which are processed into short interfering RNA molecules through different processing pathways.