Abstract Purpose of Review To summarize the mechanisms of tumor angiogenesis and resistance to antiangiogenic therapy, and the influence on tumor microenvironment. Recent Findings Several clinical trials have investigated the activity of anti-VEGF monoclonal antibodies and tyrosine kinase inhibitors in glioblastoma, shedding the light on their limitations in terms of disease control and survival. We have outlined the mechanisms of resistance to antiangiogenic therapy, including vessel co-option, hypoxic signaling in response to vessel destruction, modulation of glioma stem cells, and trafficking of tumor-associated macrophages in tumor microenvironment. Moreover, novel generation of antiangiogenic compounds for glioblastoma, including small interfering RNAs and nanoparticles, as a delivery vehicle, could enhance selectivity and reduce side effects of treatments. Summary There is still a rationale for the use of antiangiogenic therapy, but a better understanding of vascular co-option, vascular mimicry, and dynamic relationships between immunosuppressive microenvironment and blood vessel destruction is crucial to develop next-generation antiangiogenic compounds.