The reason why tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma(HCC) where alternate therapies are lacking. We recently published a paper entitled “Co-option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma” in the Journal of the National Cancer Institute, providing a potential explanation for this limited beneit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. Accumulating evidence suggests that many human tumor types may use vessel co-option, which has profound implications for the use of anti-angiogenic agents for cancer treatment. The reason why the tumors generally have a modest or transient response to antiangiogenic therapy is not well understood. This poses a major challenge for sorafenib treatment of advanced hepatocellular carcinoma (HCC) where alternate therapies are lacking. We recently published a paper entitled “Co- option of liver vessels and not sprouting angiogenesis drives acquired sorafenib resistance in hepatocellular carcinoma ”in the Journal of the National Cancer Institute, providing a potential explanation for this limited beneit. We found that in mice bearing HCCs that had acquired resistance to sorafenib, tumors had switched from using angiogenesis for growth to co-opting the liver vasculature by becoming more invasive. which has profound implications for the use of anti-angiogenic agents for cancer treatment.