Significance: Mechanical forces are important regulators of cell and tissue function. Endothelial cells proliferate in response to tissue stretch and the mechanical properties of the environment direct capillary sprouting and growth. As the vascular network is a key factor in physiology and disease, control of the vascularity by means of mechanical forces could lead to the development of innovative therapeutic strategies. Recent Advances: Increased understanding of mechanobiology has stimulated translational research and allowed the development and optimization of clinical devices that exploit mechanical forces for the treatment of diseases, in particular in the field of wound healing. Stretching in distraction osteogenesis and tissue expansion induces neogenesis of well-vascularized tissues. In micro-deformational wound therapy, micro-mechanical distortions of the wound bed stimulate cell proliferation and angiogenesis by stretching resident cells to improve healing of difficult wounds. Relief from tension antagonizes proliferation and angiogenesis in primarily closed wounds allowing for better scar quality. Critical Issues: The integration of mechanobiology into traditional cell biology and pathophysiology in general is not yet complete and further research is needed to fill existing gaps, in particular in the complexity of in vivo conditions. Future Directions: Still largely unexplored approaches based on mechanical perturbation of the micro-/macro-environment can be devised to overcome the limits of current strategies in a broad spectrum of clinical conditions.