Cationic, polymer-based delivery systems have faced limitations in the systemic delivery of therapeutic gene drugs due to difficulties in formulation, in vivo stabilization, toxicity and low transfection efficiencies. Strategies for overcoming some of these barriers have utilized knowledge gained from the fields of colloidal stabilization and protein trafficking. This review highlights recent efforts in polycation preparations that include the development of new polymers for gene delivery, the modification of traditional polycations with hydrophilic polymers for salt and serum stability and the addition of bioactive functionalities to polymers for enhanced intracellular trafficking. These studies have resulted in polymer/DNA composites with increased stability and delivery efficiencies.