ral administration and hypodermic injection are routine approaches for drug delivery to the circulation. However, they are associated with some shortcomings, such as premature drug metabolization by the first-pass effect of the liver and gut wall, degradation of drugs by the digestive tract, unstable plasma levels, difficulty of immediate termination, pain, dangerous medical waste, and risk of disease transmission by needle reuse. 1 Transporting therapeutic agents through the wide epidermis, known as transdermal drug delivery, is an attractive alternative to conventional approaches. Transdermal drug delivery is noninvasive in nature, and the systems can be self-administered, released over a long period, and inexpensive. Three generations of development have been undergone in transdermal drug delivery, such as chemical enhancers, 2 iontophoresis, 3 biochemical enhancers, 4 electroporation, 5 and microneedles. 6 These techniques are mostly reversible except microneedles. The skin structure and elasticity can be altered to enable increased permeation of compounds temporarily and resumed a few hours after termination without permanent damage. Kun Loong Lee, BS, Yufeng Zhou, PhDReceived January 14, 2014, Transdermal drug delivery makes a critical contribution to medical practice and some advantages over conventional oral administration and hypodermic injection. Enhancement of percutaneous absorption or penetration of therapeutic agents (ie, drugs and macromolecules) by ultrasound, termed sonophoresis, has been applied and studied for decades. In this study, the penetration percentage through porcine ear skin specimens was determined quantitatively by measuring the fluorescence from nanoparticles of 60, 220, and 840 nm in size in a receptor chamber at different sonication parameters (ie, duty cycle, 20%-100%; acoustic intensity, 0.3-1.0 W/cm 2 ; duration, 7-30 minutes; and frequency, 1 MHz). In general, the sonophoresis efficiency increased with the acoustic intensity, duty cycle, and sonication duration but decreased with the particle size (mean ± SD, 62.6% ± 5.4% for 60-nm versus 11.9% ± 1.1% for 840-nm polystyrene nanospheres after 30 minutes of sonication at 0.5 W/cm 2 and a 100% duty cycle; P < .05). On scanning electron microscopy the pore size remained the same (≈100 μm), but more flakes were observed with the progress of sonication. In summary, sonophoresis efficiency is dependent on the ultrasound parameters and particle size. Sufficient sonication would lead to satisfactory penetration of even submicrometer objects through the pores.