Purpose: An estimated $170 billion is spent annually on biomedical devices including pacemakers, implants for reconstructive surgery and biosensors around the world. Implantable materials used in biomedical devices elicit a host response termed foreign body response (FBR). FBR begins as a wound healing response but progresses into a fibrotic reaction resulting in the formation of a fibrous capsule, which isolates the implant from the surrounding microenvironment leading to implant failure. As advances are made in materials sciences, electronics, and design of sophisticated biomedical devices, modulating FBR remains the final frontier in developing durable man-machine interfaces. One key component of fibrosis that is often overlooked in the study of FBR is mechanical signaling. We have previously shown that fibrotic wound healing does not occur under normal conditions in mice, but when healing wounds are subject to high levels of mechanical stress, they produce human-like fibrotic scar tissue. Since wound healing and FBR are very closely related pathologies concluding in a fibrotic reaction characterized by increased collagen deposition, we hypothesized that mechanical signaling is a critical component of FBR to implantable materials. Methods: FBR capsules from humans (breast implants, pacemakers, and neurostimulator batteries) and mice were analyzed using immunohistochemistry. Subsequently, we quantified the local mechanical stress patterns that emerge at the implant-tissue interface in both mice and humans using computational finite element modeling. To further test our hypothesis, we developed vibration-enabled implants (VEIs), which recapitulate human levels of mechanical stress in mice via in situ vibration of silicone implants. We then compared FBR in control mice, VEI model, and humans. Next, we used mass spectrometry to identify the mechanotransduction pathways that are upregulated in the VEI model. Finally, experiments using WT and IQGAP1 KO mice verified the critical role of mechanotransduction in FBR. Single cell sequencing experiments and immunostaining of FBR tissue were employed to study FBR in WT and KO mice. Results: We demonstrate that the differences in FBR between mice and humans is a result of differential mechanical stress at the implant-tissue interface. Applying human levels of mechanical stress around murine implants using VEIs results in human-like robust FBR, which proves that mechanical stress is a critical component of human FBR. Proteomics analyses revealed that IQGAP1, which is a scaffolding protein involved in multiple mechanotransduction pathways is upregulated in VEI capsules as compared to control subcutaneous tissue. Here we show that IQGAP1 KO mice reverse the effect of mechanically enhanced FBR. Finally, single cell sequencing experiments identified critical mechanoresponsive subpopulations of macrophages and fibroblasts that were underrepresented in the KO mice, further confirming that targeting mechanotransduction is a viable means to reduce FBR to biomedical implants. Conclusion: Here we demonstrate the central role of mechanical signaling at the implant-tissue interface in human FBR. Further studies are underway to develop therapeutic strategies to limit FBR. These findings reveal the importance of modulating the mechanical environment to improve the in vivo biocompatibility of biomedical devices.