Adenoviral (Ad) vectors possess many attributes that have lead to their use as gene delivery agents in human clinical trials. However, gene transfer efficiency has generally been less than that needed for meaningful clinical responses. The restricted tropism of the virus for its native receptor, the coxsackie and adenoviral receptor (CAR), is emerging as a key limitation to the use of these agents. By developing strategies to achieve Ad infection via alternate receptor pathways, enhanced and more specific gene delivery can be achieved. This new generation of tropism-modified agents holds promise for the improved clinical utility of Ad vectors for gene therapy.