Drugs that can be activated by a physical stimulus at a target site offer great potential for limiting toxic side effects, e.g., in cancer therapy. In photodynamic therapy, light is used as the stimulus, but clinical applications are limited due to the poor penetration of light in tissue. Multiple studies have demonstrated that ultrasound can also be used to activate some light-responsive drugs. This potentially extends the range of therapeutic applications considerably, but the mechanisms underpinning drug activation, dubbed sonodynamic therapy (SDT), remain unclear. It was recently demonstrated that multi-bubble sonoluminescence could be detected from a suspension of microbubble ultrasound contrast agents when exposed to ultrasound under conditions similar to those used in SDT. Moreover, the addition of an SDT drug produced a reduction in optical emissions at the wavelength corresponding to its activation. Numerous questions, however, remain and the aim of this talk is to review recent studies of SDT and new evidence for the roles of sonoluminescence, sonoporation, and other phenomena hypothesized to play a role in its mechanism of action.