Helper-dependent adenoviral vector (HDAd) lacking all viral coding sequences with the advantages of minimal immunogenicity, negligible chronic-toxicity, and durable transgene expression over first-generation adenoviral vector (FGAd). HDAd vehicles have demonstrated tremendous potential for gene therapy in animal models for inherited diseases, neurodegenerative diseases and cancer etc. Additionally, the large cloning capacity of HdAd, up to 37 kb, permits the delivery of whole genemic loci, multiple transgenes. In this review we characterize the basic features of HdAd and summarize some of their experimental and potential clinical applications both at present and in future.