The coxsackie and adenovirus receptor (CAR) mediates viral infection by the binding of various adenoviruses through specific protein interactions. There is a high affinity between the viral knob domain and the extracellular amino- terminal domain (designated D1) of CAR. The D1 domain alone is sufficient for knob binding in transfected cells. Determining the specific interactions between CAR and adenoviruses is imperative in order to further develop gene therapy using viral hosts. CAR is expressed in many human and murine cell types. However, cells that express CAR at low levels are not efficiently infected by adenoviruses. Possible methods of avoiding this problem in certain cell types are by either supplementing CAR or modifying the Ad knob to bind to other receptors.