The concept of inhibiting tumor neovessels has taken the hurdle from the bench to the bedside and now represents an extra pillar of anticancer treatment. So far, anti-angiogenic therapy prolongs survival in the order of months in some settings while failing to induce a survival benefit in others, in part because of intrinsic refractoriness or evasive escape. This review provides an update on recent mechanisms via which tumor and stromal cells induce resistance and discusses recent evolutions in the (pre)clinical development of novel third-generation anti-angiogenic agents to overcome this problem.