Enhanced tissue permeability resulting from pulsed high intensity focused ultrasound (pHIFU) has been studied for over a decade now. Most of these studies have been in mouse models. To proceed to the clinic, two questions remain to be answered, first, what is the mechanism of action, and second, can it be scaled to humans. The goal of our ongoing research is to provide clear answers to these questions. An Insightec ExAblate 2000 3T MR guided focused ultrasound device was used to sonicate the thigh muscle of rabbits. The sonication parameters were similar to those successfully used in the many earlier mouse studies. Experimental work was supplemented with theoretical modeling to test earlier assumptions regarding tissue heating and radiation force induced strains in computer models of mouse and bulk muscle. Our results suggest that the thermal dose, rather than peak acoustic or half-harmonics power, appears as the best indicator of improved transport. These studies indicate that the parameters and assumptions from earlier studies in mouse models must be re-evaluated for larger animals and humans.