Therapies targeting tumor angiogenesis are used in a variety of malignancies, however not all patients benefit from treatment and impact on tumor control may be transient and modest. Mechanisms of resistance to anti-angiogenic therapies can be broadly categorized into VEGF-axis dependent alterations, non-VEGF pathways, and stromal cell interactions. Complimentary combinations of agents that inhibit alternative mechanisms of blood vessel formation may optimize inhibition of angiogenesis and improve clinical benefit for patients. The purpose of this review is to detail the preclinical evidence for mechanisms of angiogenic resistance and provide an overview of novel therapeutic approaches exploiting these pathways.