Recombinant retroviruses are a commonly used gene delivery tool in human gene therapy clinical trials as they permanently integrate the therapeutic DNA into the genome of the target cell. Despite their widespread use, however, retroviral gene transfer efficiencies remain disappointingly low. In the years since their initial development as vectors, it has become clear that the physicochemical properties of the recombinant retrovirus, as well as the properties of the target tissue, have a major impact on the success of gene transfer. In particular, the interaction between the native negative charge present on the vector and target cell membranes results in a significant electrostatic barrier which must be overcome in order for the transduction process to begin. Using a recently developed retrovirus adsorption assay, we have demonstrated that this electrostatic interaction is the dominant interaction during the initial steps of transduction. We have also established that cationic polymers enhance adsorption, and ostensibly transduction, by neutralizing this electrostatic barrier. Interestingly, we also found that this enhanced adsorption could be demonstrated even in the absence of a cellular receptor for the virus, suggesting that the first step of transduction does not involve binding of the virus to currently identified receptors, but is either a non-specific adsorption process or involves binding to an, as of yet, uncharacterized class of receptor. Based upon our finding that virus adsorption is non-gp70 mediated, we propose a new physical model of this initial step of transduction which is diffusion-limited, receptor and envelope independent, and modulable by positively charged compounds. Our findings may have significant implications for other gene and drug delivery systems which interact directly with target tissues at the level of the cell membrane.