The majority of recent preclinical gene therapy studies targeting the retina have used adeno-associated virus (AAV) as the gene transfer vector. However, AAV has several limitations including the ability to generate innate inflammatory responses, the ability to cause insertional mutagenesis at a frequency of up to 56% in some tissues and a limited cloning capacity of 4.8Kb. Furthermore, AAV is known to generate limiting immune responses in humans despite the absence of similar immune responses in preclinical canine and murine studies. Three clinical trials to treat Leber's congenital amaurosis using AAV are under way. A clinical trial to treat Stargardt's using lentivirus vectors has also been recently announced. However, very limited evidence currently exists that lentivirus vectors can efficiently transduce photoreceptor cells. In contrast, very few preclinical ocular gene therapy studies have utilized adenovirus as the gene therapy vector. Nonetheless, the only two ocular gene therapy clinical trials performed to date have each used adenovirus as the vector and more significantly, in these published trials there has been no observed serious adverse event. These trials appear to be poised for Phase II/III status. Activation of cytotoxic T lymphocytes limits duration of transgene expression in the retina from first generation adenovirus vectors. However, an advanced class of adenovirus vectors referred to as Helper-dependent Adenovirus (Hd-Ad) have recently been shown to be capable of expressing transgenes in ocular tissues for more than one year. Hd-Ad vectors have many properties that potentially warrant their inclusion in the retinal gene therapy toolbox for the treatment of retinal degenerative diseases.