With the recent explosion of genomic information on the root causes of disease， there is an increased interest in nucleic acid therapeutics， including siRNA and gene therapy， all of which require delivery of highly charged nucleic acids from siRNA with a molecular weight of about 1.4?×?10 to plasmids with an approximate molecular weight of 2.0-3.0?×?10. This chapter describes the delivery of shRNA via plasmid or siRNA with a peptide-based carrier. We focus on the histidine-lysine peptide which serves as an example for other peptides and polymeric carrier systems. When the HK peptide and nucleic acids are mixed together and interact with one another through ionic and nonionic interactions， nanoplexes are formed. These nanoplexes， carrying either shRNA or siRNA that target oncogenes， provide promising options for the treatment of cancer. We describe methods of preparation and characterization of these nanoplexes using dynamic light scattering， zeta potential， and gel retardation assays. We also provide protocols for transfection in vitro and in vivo for these nanoplexes.