Antiangiogenesis was proposed as a cancer therapy over 20 years ago and the list of compounds reported to possess antiangiogenic activity is extensive. Inhibitors are grouped as specific and non-specific, depending on whether they inhibit proliferation and/or migration of endothelial cells only or are also cytotoxic for tumor cells. Antiangiogenic therapy is applicable to a wide variety of solid and hematological tumors and there is evidence that tumors do not develop resistance to its effects due to the low mutagenic potential of endothelial cells. It is too early to predict whether antiangiogenesis will be of benefit in hematological malignancies. Strategies that target both the stromal and tumor compartments, such as combining traditional cytotoxic chemotherapy with antiangiogenic agents, may indeed have an impact on drug resistance and improve the therapeutic response. Conventional chemotherapeuticals used at very low doses, strikingly and reversibly impact on certain endothelial cell functions without nonspecific cytotoxic or necrotic damage. The use of low doses in “metronomic” chemotherapy (namely, very frequent or continuous low-dose chemotherapy) as antiangiogenic targeting strategy seem particularly effective against drug-resistant tumors, especially when combined with a secondary antiangiogenic drug. Further studies are needed to secure the comprehensive understanding and to elucidate the molecular basis of the use of these new therapeutic approaches in the treatment of hematological malignancies that actually are suboptimally treated with conventional cytotoxic therapy.