There is interest in harnessing the energy from ultrasound‐microbubble interactions for therapeutic gain. Microbubbles (MB) can be used as vectors for ultrasound mediated gene delivery (UMGD). This process relies on coupling cDNA to MB that undergo cavitation resulting in delivery∕transfection from controlled bioeffects. Proximity of gene‐laden MB to the vessel wall is a critical determinant of UMGD, which may be enhanced by the use of targeted MB probes that bind to certain disease states. In this presentation, endothelial targeting strategies will be discussed together with their recent application to optimize UMGD. Flow chamber and intravital microscopy studies have been performed that demonstrate that the coupling of cDNA and MB surfaces does not interfere with binding of these agents to counterligands on the vascular endothelium. Imaging experiments have also been performed demonstrating that MB retention in tissue using an ischemia‐targeting approach is possible with gene‐laden MBs targeted to endothelial cell adhesion molecules. Finally, data on the relative transfection efficiency of reporter genes with UMGD using a targeted versus control MB vector approach will be discussed. The overall conclusion of the presentation is that the ability to target MB to disease‐related molecules may increase both efficiency and specificity of tissue transfection.