Adenoviruses have been widely employed for a variety of gene therapy applications, owing largely to their unparalleled efficiency in accomplishing in vivo gene transfer. Despite this unique capacity, full use of these vectors for gene therapy applications has been limited by their reliance on target cell entry via the native adenovirus receptor, CAR. On this basis, target cells which express low amounts of CAR are relatively resistant to adenoviral vectors (Ad). Alternatively, recognition of CAR may allow gene transfer via Ad to ectopic target cell sites with attendant toxic/morbid consequences. Thus, the ability to direct adenovirus to cell-specific receptors, in a CAR-independent manner, would potentially allow circumvention of these two key limitations of Ad vectors. To this end, we have endeavored tropism-modifications of Ad to allow cell-specific gene delivery. This has been achieved via heterologous retargeting complexes and via genetic modification of the Ad capsid. Both of these strategies have allowed the achievement of CAR-independent gene delivery to target cells. Further, such CAR-independent gene delivery has allowed the achievement of both cell-specific gene delivery as well as gene transfer efficiency augmentations. On this basis, it is clear that strategies to alter Ad tropism may allow greatly improved utilities of Ad for gene therapy applications.