The article discusses the modes of resistance to anti-angiogenic therapy, focusing on two primary mechanisms: evasive resistance and intrinsic or pre-existing indifference. Evasive resistance involves the tumor's adaptation to circumvent the specific angiogenic blockade, while intrinsic resistance is the tumor's inherent lack of responsiveness to anti-angiogenic treatments. The authors highlight multiple mechanisms that can lead to both types of resistance, including upregulation of alternative pro-angiogenic signaling pathways, recruitment of bone marrow-derived pro-angiogenic cells, increased pericyte coverage of the tumor vasculature, and increased invasiveness without angiogenesis. They also explore the potential for pre-existing multiplicity of redundant pro-angiogenic signals, inflammatory cell-mediated vascular protection, and the co-option of normal vessels without angiogenesis. The article emphasizes the need for further research to understand these mechanisms and develop strategies to overcome them, such as combining anti-invasive and anti-metastatic drugs with anti-angiogenic treatments. Despite the limitations of current anti-angiogenic therapies, the authors see promise in their potential to improve cancer treatment.The article discusses the modes of resistance to anti-angiogenic therapy, focusing on two primary mechanisms: evasive resistance and intrinsic or pre-existing indifference. Evasive resistance involves the tumor's adaptation to circumvent the specific angiogenic blockade, while intrinsic resistance is the tumor's inherent lack of responsiveness to anti-angiogenic treatments. The authors highlight multiple mechanisms that can lead to both types of resistance, including upregulation of alternative pro-angiogenic signaling pathways, recruitment of bone marrow-derived pro-angiogenic cells, increased pericyte coverage of the tumor vasculature, and increased invasiveness without angiogenesis. They also explore the potential for pre-existing multiplicity of redundant pro-angiogenic signals, inflammatory cell-mediated vascular protection, and the co-option of normal vessels without angiogenesis. The article emphasizes the need for further research to understand these mechanisms and develop strategies to overcome them, such as combining anti-invasive and anti-metastatic drugs with anti-angiogenic treatments. Despite the limitations of current anti-angiogenic therapies, the authors see promise in their potential to improve cancer treatment.