Angiogenesis, the process of new blood vessel formation, is a critical component of tumor growth and metastasis. While therapeutic strategies targeting vascular endothelial growth factor (VEGF) and its receptors have shown initial promise in cancer treatment, their effectiveness has been limited by issues such as resistance and adverse side effects. Recent advances have highlighted the complexity of angiogenesis, with the identification of VEGF isoforms that exhibit distinct roles in both pro- and antiangiogenic activities. Importantly, VEGF165a promotes sprouting angiogenesis and intussusceptive vascular remodeling, while VEGF165b acts as an inhibitor of VEGF165a binding to VEGFR-2. Additionally, tumor-associated stromal factors, such as thrombospondin-1 (Tsp-1), CD36, and CD47, influence angiogenesis through multifaceted signaling pathways. These findings highlight the complex interplay between tumor and stromal cells in regulating angiogenesis. Given the genomic stability of stromal cells, targeting the tumor microenvironment (TME) and its associated angiogenic factors offers a promising therapeutic strategy. Further exploration of VEGF isoforms, splice variants, and TME signaling pathways could lead to more effective, targeted therapies with reduced resistance and improved clinical outcomes. This evolving landscape of antiangiogenic therapy presents novel opportunities to inhibit tumor growth while minimizing the challenges seen with traditional therapeutic approaches.