The potential epidemiological human pandemic resulting from highly pathogenic avian influenza (HPAI) H5N1 has been studied extensively since the identification of the virus in the Guangdong province of China. The majority of research has focused on the unique and severe histopathological lesions induced by the virus. The severe pathological presentation of these infections has also prompted interest in identifying preventive and therapeutic approaches against HPAI. The potential severity of a HPAI pandemic and the efforts to identify effective intervention strategies have led to many novel discoveries in vaccine and antiviral development that are critically examined in this review.