Microbubble (MB) mediated ultrasound (US) therapy has been shown to non-invasively increase drug uptake through increasing cell membrane permeability and vascular extravasation. Increasing MB-cell interaction through targeted receptors overexpressed in the tumor vasculature promises to increase effectiveness of MB-mediated US therapy. 2LMP breast cancer cells were plated on acoustically transparent tissue culture plates. Using a model system which allows receptor density modulation, molecular US therapy was analyzed for anticancer effects in vitro. Drug (paclitaxel) effectiveness in combination with traditional MB-mediated US therapy or molecular US therapy was analyzed using flow cytometry and ATPlite assays. It was shown that molecular US therapy significantly increases anticancer effects by 25% compared to traditional MB-mediated US therapy (P < 0.001). This preclinical approach has potential to increase localized delivery through a targeted methodology, thereby potentially decreasing systemically toxicity. This study demonstrates that MBs targeted to cellular receptors are a promising addition to MB-mediated US therapy.