Purpose <p>A requirement for effective chemotherapy is that therapeutic agents reach all cancer cells. However, only a small fraction of the dose accumulates in tumors and is taken up by cancer cells. Encapsulation of drugs into nanoparticles, exploiting the enhanced permeability and retention effect, has moderately improved tumor accumulation. The nanoparticles, being substantially larger than molecular drugs, encounter more severe obstacles in reaching the tumor cells resulting in heterogeneous tumor distribution. Delivery of drugs to the brain is even more challenging due to the blood-brain barrier.</p> Methods <p>In this review, we describe the various barriers for successful delivery of nanoparticles, including the chaotic vasculature, heterogenous extravasation and dense extracellular matrix the nanoparticles need to penetrate. Ultrasound has been shown to enhance delivery of therapeutic agents across these barriers, and the various mechanisms for ultrasound-mediated drug delivery are discussed.</p> Results <p>The transport of nanoparticles is governed by diffusion and convection, depending on the concentration- and hydrostatic pressure gradient, respectively. Elevated interstitial fluid pressure within tumors eliminates the transcapillary pressure gradient except at the tumor periphery, and pressure gradients within the interstitial space are largely absent. Consequently, diffusion becomes the dominant transport mechanism, but diffusion of nanoparticles is inherently slow. Ultrasound combined with circulating microbubbles has been reported to improve the delivery of therapeutic agents, resulting in improved therapeutic outcomes. This has been shown both for tumors outside the brain and for tumors and other diseases in the brain. Ultrasound and microbubbles can enhance extravasation by increasing both paracellular and transcellular transport, which is particularly important for crossing the blood-brain barrier. Oscillations of the vascular wall induced by ultrasound and microbubbles can improve fluid flow through the extracellular matrix. Increased interstitial hydraulic conductivity and reduced solid stress, associated with enhanced delivery of nanoparticles, have been reported. In addition, ultrasound alone (no microbubbles) can enhance diffusion by releasing nanoparticles bound to extracellular matrix components.</p> Conclusion <p>Understanding the underlying mechanisms of ultrasound–mediated drug delivery is essential for optimizing therapeutic outcomes. Integrating experimental data with computational modeling provides powerful tools for generating new mechanistic insights. Rakesh Jain and colleagues have been instrumental in advancing this integrated approach by developing sophisticated mathematical models and simulation frameworks alongside with advanced experimental techniques. Their research has provided new insights into key transport processes and parameters which are highly valuable for elucidating the fundamental mechanisms governing ultrasound-mediated transport.</p>