Success with clinical application of anti-angiogenesis therapy to cancers has been modest. Tumor resistance to such therapy, for example, with bevacizumab, is attributed to tumor reliance on angiogenic pathways that are alternatives to VEGF, selection of hypoxia-tolerant, HIF-1α-producing tumor cells, contributions from stem cells or dormancy of tumor cells during anti-VEGF therapy. We have proposed that in cancer patients there are additional host factors with inherent pro-angiogenic properties that oppose therapeutic anti-angiogenesis. Examples of such factors are estrogen, androgen and thyroid hormone. Physiological concentrations of thyroid hormone—3,3′,5′-triiodo-L-thyronine (T3) and L-thyroxine (T4)—initiate their multi-mechanism, pro-angiogenic activity via a cell surface receptor site on integrin αvβ3 on dividing endothelial cells and tumor cells. We will review here the mechanistic pathways in the pro-angiogenic action of thyroid hormone that may limit success of anti-angiogenesis treatment. Our recent results are obtained in the model of human ovarian cancer cells. The treatment of ovarian cancer cells with T3 (1 nM) and T4 (100 nM) produced an αvβ3-mediated increase in cell viability, cell number, cell survival as well as ERK activation. The mRNA abundance and protein level of HIF-1α, a potent angiogenesis inducer, was upregulated following T3 and T4 treatments. We found that several anti-angiogenic genes are potently and quickly (1 h) inhibited in the presence of the hormones, particularly in ovarian cancer cells with high integrin expression; these genes include p16, GDF15 as well as IGFBP-6. The suppression of the latter gene correlated with a parallel increase in b-catenin, a protein which augments angiogenesis and was recently shown to potently inhibit the expression of IGFBP-6. By using HEK293 avb3 deficient or expressing cells, we have revealed that T4, but not T3, phosphorylates tyrosine 759 in the b3 subunit. This phosphorylation event not only controls outside-in signaling by the integrin, but also is the regulatory switch accommodating the proangiogenic cooperative binding interaction between VEGFR-2 and αvβ3. These new findings compliment results from our own and other laboratories showing enhancement by thyroid hormone of pro-angiogenic bFGF and VEGFA gene transcription, stimulatory crosstalk between the integrin and adjacent receptors for VEGF, bFGF, PDGF and EGF, transcription of MMP genes relevant to blood vessel formation, endothelial cell migration and release of vascular growth factors. Thus, thyroid hormone is a potent endogenous pro-angiogenesic factor which we propose contributes to clinical resistance to current antiangiogenic treatments. Disruption of the thyroid-hormone-integrin axis is anti-angiogenic and may support clinical actions of specific anti-angiogenic drugs in cancer.