Angiogenesis is essential for tumor growth and metastasis, and anti-angiogenic drugs targeting the VEGF pathway are used in oncology. However, tumors can evade these therapies through alternative angiogenesis mechanisms, such as sprouting angiogenesis, vasculogenic mimicry, vessel intussusception, vascular co-option, cancer stem cell-derived angiogenesis, and bone marrow-derived angiogenesis. These mechanisms are not always dependent on the VEGF pathway and are linked to drug resistance and treatment failure. Recent studies highlight the complexity of tumor angiogenesis, involving various cell types and signaling pathways. Anti-angiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have shown promise in clinical settings, but resistance remains a challenge. Combination therapies with immunotherapy are being explored to enhance efficacy. Understanding these mechanisms is crucial for developing more effective anti-angiogenic treatments. This review summarizes the key mechanisms of tumor angiogenesis and discusses current challenges and future directions in anti-angiogenic therapy.Angiogenesis is essential for tumor growth and metastasis, and anti-angiogenic drugs targeting the VEGF pathway are used in oncology. However, tumors can evade these therapies through alternative angiogenesis mechanisms, such as sprouting angiogenesis, vasculogenic mimicry, vessel intussusception, vascular co-option, cancer stem cell-derived angiogenesis, and bone marrow-derived angiogenesis. These mechanisms are not always dependent on the VEGF pathway and are linked to drug resistance and treatment failure. Recent studies highlight the complexity of tumor angiogenesis, involving various cell types and signaling pathways. Anti-angiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have shown promise in clinical settings, but resistance remains a challenge. Combination therapies with immunotherapy are being explored to enhance efficacy. Understanding these mechanisms is crucial for developing more effective anti-angiogenic treatments. This review summarizes the key mechanisms of tumor angiogenesis and discusses current challenges and future directions in anti-angiogenic therapy.