Our laboratory focuses on the development of activatable nanotherapeutics and the related imaging and activation technologies. We will report on recent progress with a range of constructs including dendrimers, liposomes and microbubbles, as well as the development of systems coupling magnetic resonance imaging or computed tomography with ultrasound. There are many technical challenges in vehicle activation—- the delivery vehicle should ideally be stable within the blood stream facilitating accumulation at the treatment site, energy must be accurately directed to the site with a dose that is adequate for release without producing unwanted bioeffects, and the volume of drug delivered to the site should be accurately quantified and meet the scheduled dose. In order to meet these challenges in a systematic fashion, we have developed infrastructure including combined imaging and therapy, real-time feedback, radiolabeled particles that can be imaged to guide therapy, and optical labels that change in proportion to the volume of material released. We find that it is feasible to accumulate particles totaling up to 20% of the injected dose within murine model tumors, to use positron emission tomography to guide an ultrasound beam, to release a model drug within seconds to minutes, and to detect release via near infrared optical imaging. We apply our methods in the treatment of cancer, neurodegenerative disease and atherosclerosis and will describe several recent successes. For example, we have harnessed these methods to develop a stable carrier for doxorubicin that effectively treats aggressive cancers while greatly decreasing systemic toxicity.