The purpose of this study was to develop a unified model capable of explaining the mechanisms of interaction of ultrasound and biological tissue at both the diagnostic nonthermal, noncavitational (<100 mW·cm −2) and therapeutic, potentially cavitational (>100 mW·cm −2 ) spatial peak temporal average intensity levels. The cellular-level model (termed "bilayer sonophore") combines the physics of bubble dynamics with cell biomechanics to determine the dynamic behavior of the two lipid bilayer membrane leaflets. The existence of such a unified model could potentially pave the way to a number of controlled ultrasound-assisted applications, including CNS modulation and blood-brain barrier permeabilization. The model predicts that the cellular membrane is intrinsically capable of absorbing mechanical energy from the ultrasound field and transforming it into expansions and contractions of the intramembrane space. It further predicts that the maximum area strain is proportional to the acoustic pressure amplitude and inversely proportional to the square root of the frequency (ε A;max ∝ P 0:8 A f − 0:5 ) and is intensified by proximity to free surfaces, the presence of nearby microbubbles in free medium, and the flexibility of the surrounding tissue. Model predictions were experimentally supported using transmission electron microscopy (TEM) of multilayered live-cell goldfish epidermis exposed in vivo to continuous wave (CW) ultrasound at cavitational (1 MHz) and noncavitational (3 MHz) conditions. Our results support the hypothesis that ultrasonically induced bilayer membrane motion, which does not require preexistence of air voids in the tissue, may account for a variety of bioeffects and could elucidate mechanisms of ultrasound interaction with biological tissue that are currently not fully understood.A central hypothesis regarding nonthermal interactions of ultrasound (US) energy and biological tissue is that they are primarily mediated by cavitation, that is, the activity in the US field of gas bubbles generated from submicron-sized gas pockets known as cavitation nuclei: their steady pulsations (stable cavitation) or rapid collapse (inertial cavitation) (1) and their interaction with cells, tissue, and organs (2-4). Nevertheless, this hypothesis has major limitations because low-intensity noncavitational US exposures of <100 mW·cm −2 , spatial peak temporal average (SPTA), have also been shown to induce bioeffects in cells and tissues without evidence of inertial or stable cavitation being present (3-5). On the other hand, whereas the source of in vivo cavitation is not clear, the bilayer membrane seems to be associated with many of the cellular bioeffects at a wide range of US intensities: from excitation of neuronal circuits [3 W·cm −2 spatial peak temporal peak (SPTP), 0.44 MHz] (6) to increased transfection rates in smooth muscle cells (400 mW·cm −2 SPTP, 1 MHz) (7). Our objective here is to introduce a unique hypothesis of direct interaction between the oscillating acoustic pressure and the cellular bilayer memb...