Sonoporation, ultrasound-induced plasma membrane poration, permits the passage of extracellular agents into the cytoplasm that may otherwise be impermeable, thereby making it useful for drug and gene delivery. Ca2+ is an important second messenger (signaling) molecule found to play a role in cell recovery after sonoporation. To better understand the dynamical responses of cells to sonoporation, calcium imaging of Chinese hamster ovarian cells was performed using digital video fluorescence microscopy and the Ca2+-indicator dye fura-2AM. Spatiotemporal evolution of intracellular [Ca2+]i was determined from real-time fluorescence measurements of cells in the presence of OptisonTM microbubbles and various extracellular [Ca2+]o levels before, during, and after exposure to 1 MHz ultrasound tone bursts (0.2 s, 0.45 MPa). In cells where ultrasound caused a direct microbubble-cell interaction, breaking and eventual dissolution of the microbubble were observed with concomitant permeabilization of the cells to Ca2+. These cells exhibited a large influx of Ca2+, and sometimes the [Ca2+]i did not return to its equilibrium level. Subsequently, other surrounding cells often exhibited complex [Ca2+]i dynamics, including intracellular oscillations and intercellular waves. Efforts to model the time evolution of [Ca2+]i in individual cells with analytical and numerical approaches will also be discussed. [Work supported by ACS and NIH.]