Intravital microscopy has provided unprecedented insights into tumor pathophysiology, including angiogenesis and the microenvironment. Tumor vasculature shows an abnormal organization, structure, and function. Tumor vessels are leaky, blood flow is heterogeneous and often compromised. Vascular hyperpermeability and the lack of functional lymphatic vessels inside tumors causes elevation of interstitial fluid pressure in solid tumors. These abnormalities form physiological barriers to the delivery of therapeutic agents to tumors and also lead to a hostile microenvironment characterized by hypoxia and acidosis, which hinders the effectiveness of anti-tumor treatments such as radiation therapy and chemotherapy. In addition, host-tumor interactions regulate expression of pro- and anti-angiogenic factors, resulting in pathophysiological characteristics of the tumor. On the other hand, in a physiological setting, angiogenic vessels become mature and form long-lasting functional units. Restoring the balance of pro- and anti-angiogenic factors in tumors may “normalize” tumor vasculature and thus improve its function. Administration of cytotoxic therapy during the vascular normalization would enhance its efficacy.