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Molecular imaging with ultrasound contrast has relied on targeting microbubbles to receptors of interest expressed on the vascular surface of endothelial cells.This is mostly because microbubbles cannot exit the vascular space to interrogate other surfaces, such as tumor cells.This presentation will describe two novel approaches that activate microbubbles from being minimally visible to becoming fully active when they encounter an enzyme,and another that generates microbubbles de novo when nanoparticles encounter inflamed tissue or tissue with ischemic reperfusion injury.