Biological effects of low frequency ultrasound: health hazards and medical applications Joachim H. Nagel Low frequency ultrasound is fast becoming a non-invasive tool for locally altering living tissues. There are world-wide efforts to develop techniques for mediating local cellular events in the body towards therapeutic goals as, for example, localized drug delivery, gene therapy and angiogenesis. The techniques are based on using ultrasound to selectively apply local micro-forces on cell membranes that act as shear stresses on the surface without causing irreversible damage to the target cells or the surrounding tissue to bring about various therapeutic benefits such as increased permeability of the cell membrane including sonoporation. It is generally assumed that the biological effects and biocompatibility of ultrasound and the safety of medical ultrasound equipment have long been investigated, and that limits for safe exposure to ultrasound have been established. However, almost all investigations leading to the currently valid safety limits have been using US frequencies above 500 kHz, the traditional frequency range of medical ultrasound, while these days more and more medical as well as industrial applications of ultrasound are using the low frequency part of the US spectrum, mainly between 20 kHz and 100 kHz, though it has not been verified whether the current regulations for the safe use of ultrasound equipment are valid at these frequencies. The biological effects of low frequency ultrasound have only recently been explored. According to our current knowledge they represent serious health hazards, but they also offer the potential for new, spectacular medical applications for diagnosis and treatment of diseases. Possible negative effects of high intensity low frequency ultrasound are hearing loss, impairment of the vestibular system, damage to peripheral sensory receptors, destruction of cells and fragmentation of DNA, uncontrolled sonoporation, and health problems caused by longtime stress exposure when working with ultrasonic equipment at low frequencies since ultrasound can be perceived by humans even beyond 50 kHz. Investigations of these effects will be presented as well as their consequences, including the determination of safe exposure levels. An interesting question is how the interactions between ultrasound and cells can be controlled in such a way that the potentially dangerous biological effects can be utilized to develop completely new medical applications of low frequency ultrasound. Mainly three aspects are currently under investigation: improved drug delivery using sonoporation for applications such as radionuclide tumor therapy, non-invasive cell therapy using techniques such as microbubble-enhanced ultrasound for vascular gene delivery and ultrasound controlled enhanced gene expression. In this presentation we will review the exciting developments of therapeutic low frequency ultrasound.