Highly pathogenic avian influenza A (HPAI) viruses, specifically H5N1 strains, cause widespread morbidity and mortality in domestic and wild bird populations, and recent outbreaks have resulted in severe economic losses. Although still largely confined to birds, more than 300 human cases resulting in deaths have been reported to the World Health Organization. These sporadic human cases result from direct transmission from infected birds; however, a sustained outbreak of HPAI H5N1 increases the potential for the emergence of a human pandemic strain. One approach to the containment of HPAI H5N1 is the development of vaccines for use in poultry. Currently, the majority of avian influenza vaccines for poultry are traditional whole-virus vaccines produced in eggs. Although highly efficacious, these vaccines are hindered by long production times, inflexibility in quickly altering antigenic composition, and limited breadth of protection. Newer vaccines with more efficient manufacturing processes, enhanced efficacy, and cross-protection against multiple strains would improve preparedness. Reverse genetics technology has provided one such method, and emerging gene-based vaccines offer another approach that reduces dependence on egg-based production and human exposure to pathogenic viruses. Gene-based vaccines also provide rapid manufacturing, enhanced precision and versatility, and the capacity to protect against a broad range of viral subtypes. Vectors for these vaccines include replication-defective viruses, bacterial vectors, and DNA. Here we review the features of gene-based vaccination that may facilitate the control of HPAI H5N1 in poultry, and highlight the development of a hemagglutinin-based multivalent DNA vaccine that confers protection in mice and chickens.