Angiogenesis is critical for growth of many tumor types and the development of anti-angiogenic agents opened a new era in cancer therapy. However, similar to other anti-cancer therapies, inherent/acquired resistance to anti-angiogenic drugs may occur in cancer patients leading to disease recurrence. Recent studies in several experimental models suggest that both tumor and non-tumor (stromal) cell types may be involved in the reduced responsiveness to the treatments. The current review focuses on the role of stromal cells in tumor growth and in refractoriness to anti-VEGF treatment.