The present invention provides methods for designing a sequence for efficient short interference RNA molecules. In particular, the present invention defines a universal target for siRNA derived from the consensus sequence of the polyadenylation signal in conjunction with unique sequences for gene silencing and inhibition of viral replication in a eukaryotic host cell. The present invention further provides methods for the treatment and prevention of diseases and disorders by silencing a gene of a virus, an oncogene, genes encoding transcription factors and many other diseases related genes.