Diabetes and peripheral arterial disease affect hundreds of millions of people worldwide. Patients with these conditions frequently develop chronic wounds on the lower limbs that lead to amputation, with a 5-year mortality rate as high as 77%. Macrophages, the primary cell of the innate immune system, are critical regulators of angiogenesis and wound healing. Their dysfunction is strongly implicated in arterial dysfunction, limb ischemia, and poorly healing chronic wounds. The goal of the Biomaterials and Regenerative Medicine Laboratory at Drexel University is to understand the mechanisms by which macrophages orchestrate successful angiogenesis and tissue regeneration and to develop novel biomaterial strategies that apply these principles to pathological situations, in order to ultimately prevent limb amputation. This talk will focus on the effects of temporal changes in macrophage phenotype on angiogenesis, the design of biomaterials and drug delivery systems to modulate macrophage phenotype for enhanced angiogenesis, and the development of macrophage phenotype-related biomarkers to assist in clinical decision making for a personalized medicine approach to wound care.