Ultrasound, especially at low frequencies, is very effective in permeabilizing the skin (Tezel et al. 2001) . It is now understood that acoustic cavitation, which is formation, pulsation, and collapse of gaseous bubbles under the oscillating pressure field of ultrasound, is the principal mediator for ultrasound-induced enhanced skin permeability. Several studies have shown that during ultrasound exposure, transient cavitation is predominantly induced in the coupling medium (the liquid present between the ultrasound transducer and the skin) and is primarily responsible for skin permeabilization (Tang et al. 2002; Tezel et al. 2002; Tezel and Mitragotri 2003 ). An estimated 10 bubble collapses/s/cm 2 in the form of symmetric collapses Fig. 4 Skin permeabilization methods. a Skin abrasion device, in which a sandpaper device is placed on the skin (1), scraped across the skin in a controlled fashion (2) and then a vaccine patch is applied to the abraded skin (3) (Courtesy of Intecell). b Hand-held skin electroporation device, which uses microneedles as electrodes to cause highly localized electroporation in the skin to facilitate DNA vaccine delivery into skin cells (Courtesy of Cyto Pulse Sciences). c Heat-based device for thermal ablation of the skin. The microheater array (left side of inset) is used to ablate the skin and then a vaccine patch (right side of inset) is applied to the ablated skin (Courtesy of Altea Therapeutics) (generating shock waves) or asymmetric collapses (producing microjets) near the surface of the skin are sufficient to explain the experimentally-observed skin permeability enhancements by ultrasound-induced skin permeabilization. Ultrasound has been shown to enhance the delivery of vaccines into skin (Tezel et al. 2005) . Studies performed in mice have shown that the immune response generated by ultrasonically delivered vaccine was about 10-fold greater compared with SC injection per unit dose of the vaccine that entered the skin (about 1% of the topically applied dose entered the skin) (Tezel et al. 2005) . Compared to simple topical administration, ultrasound pretreatment showed increased vaccine delivery, thereby enabling sufficient vaccine to enter the skin to activate the immune response. Furthermore, application of ultrasound resulted in activation of Langerhans cells, the reasons behind which are not clear. In another study, it was shown that application of tetanus toxoid to skin pretreated with ultrasound generated anti-tetanus toxoid IgG and neutralizing antibody titers (Dahlan et al. 2009 ). Several parameters, including concentration of co-applied sodium dodecyl sulfate and ultrasound duty cycle, impacted the magnitude of antibody titers. The authors concluded that the main mechanism of ultrasound-assisted skin immunization involved factors in addition to enhancement of skin permeability to topically applied antigen.