The efficacy of drug-eluting stents (DES) requires delivery of potent compounds directly to the underlying arterial tissue. The commercially available DES drugs rapamycin and paclitaxel bind specifically to their respective therapeutic targets, FKBP12 and polymerized microtubules, while also associating in a more general manner with other tissue elements. As it is binding that provides biological effect the question arises as to whether other locally released or systemically circulating drugs can displace DES drugs from their tissue binding domains. Specific and general binding sites for both drugs are distributed across the media and adventitia with higher specific binding associated with the higher specific binding site densities in the media. The ability of rapamycin and paclitaxel to compete for specific protein binding and general tissue deposition was assessed for both compounds simultaneously and in the presence of other commonly administered cardiac drugs. Drugs classically used to treat standard cardiovascular diseases, such as hypertension and hypercoaguability, displace rapamycin and paclitaxel from general binding sites, possibly decreasing tissue reserve capacity for locally delivered drugs. Paclitaxel and rapamycin do not affect the other's binding to their biologically relevant specific protein targets, but can generally displace each other from tissue at three log order molar excess, decreasing arterials loads by greater than 50%. Local competitive binding therefore should not limit the placement of rapamycin and paclitaxel eluting stents in close proximity.