Abstract: Disclosed herein are siHybrids used for gene silencing. An siHybrid is a short double-stranded molecule comprised of one strand of DNA and one strand of RNA, annealed together, with a 2-base overhang at each 3′ end. In addition to DNA and RNA, it may contain PNA or other nucleic acid analogs. siHybrids can silence a gene with greater magnitude and duration than siRNA and they can also silence bacterial genes, which siRNA cannot. siHybrids are ideal candidates for pharmaceutical and therapeutic agents for treating diseases caused by an over-expressed gene or a cancerous gene. They also can be used as antibiotics when targeted to a vital and unique bacterial gene. siHybrids can be used as antivirus agents, fungicides, herbicides or pesticides. An appropriate siHybrid can be designed to silence any gene in any cell of any organism.