The article reviews the multifaceted role of the extracellular matrix (ECM) in angiogenesis, emphasizing its dynamic and reciprocal properties beyond its traditional functions as a structural material. The ECM modulates angiogenic signaling, mechanical transduction, receptor activation, and cellular behaviors, guiding the formation, maturation, and stabilization of functional vascular networks. Key ECM components, such as fibrous proteins, adhesive glycoproteins, and proteoglycans, play crucial roles in these processes. The article highlights the importance of the ECM in both physiological and pathological angiogenesis, including wound healing and tumor vascularization. It discusses the challenges in translating angiogenic factors into clinical therapeutics, particularly in wound healing and tumor angiogenesis, and explores the potential of designer pro-angiogenic biomaterials to overcome these challenges. The review also emphasizes the need for further research to bridge the gap between in vitro biomaterials and the in vivo microenvironment, aiming to develop more effective and biomimetic biomaterials and biosystems for advancing angiogenesis research and regenerative medicine.The article reviews the multifaceted role of the extracellular matrix (ECM) in angiogenesis, emphasizing its dynamic and reciprocal properties beyond its traditional functions as a structural material. The ECM modulates angiogenic signaling, mechanical transduction, receptor activation, and cellular behaviors, guiding the formation, maturation, and stabilization of functional vascular networks. Key ECM components, such as fibrous proteins, adhesive glycoproteins, and proteoglycans, play crucial roles in these processes. The article highlights the importance of the ECM in both physiological and pathological angiogenesis, including wound healing and tumor vascularization. It discusses the challenges in translating angiogenic factors into clinical therapeutics, particularly in wound healing and tumor angiogenesis, and explores the potential of designer pro-angiogenic biomaterials to overcome these challenges. The review also emphasizes the need for further research to bridge the gap between in vitro biomaterials and the in vivo microenvironment, aiming to develop more effective and biomimetic biomaterials and biosystems for advancing angiogenesis research and regenerative medicine.