It is generally thought that angiogenesis inhibitors, when applied for the treatment of cancer, show their best clinical benefit in well-designed combination approaches. Such combinations can be based on mixtures of different angiogenesis inhibitors, allowing the advantage of improved efficacy by targeting different signaling pathways [1–3]. In addition, it is believed that the risk of drug-induced resistance is reduced when inhibition is affected through multiple pathways [4]. Alternatively, the inhibition of blood vessel formation can be combined with other promising treatment regimens. Both strategies are subject of the current special issue of Angiogenesis. This special issue addresses the current and timely efforts and advances in preclinical and clinical studies in combinatorial approaches involving angiogenesis inhibitors. Six dedicated articles show different perspectives of possible alleys of improving the activity of angiogenesis inhibitors via combining them with other treatment strategies. In renal cell cancer the approval of the first angiostatic tyrosine kinase inhibitors induced a renaissance in the treatment of this disease. While this type of cancer used to be practically untreatable, the application of sunitinib showed an immediate response in about half of the patients. Although combination with other targeted drugs was either difficult or did not further improve survival, the combination with immunotherapy is currently extremely promising. Kuusk et al. [5] review the current clinical trials on combination therapies of VEGF-targeted therapy with the so-called immune checkpoint inhibitors in metastatic renal cell carcinoma. Another paper by Ramjiawan et al. [6] continues on the importance of immunotherapy in combination with anti-angiogenic agents and addresses the mechanisms of reprogramming the tumor microenvironment in order to enhance tumor autoimmunity and circumvent resistance to angiostatic drugs. A different insight into current angiostatic combination trials in the clinic is provided by Hamming et al. [7], providing an overview of the combination of radiotherapy with angiostatic agents. The authors elegantly discuss the results of recently performed clinical trials. Bani et al. [8] explore the mechanisms of anti-angiogenic tyrosine kinase inhibitors in combination with chemotherapeutics. In a set of new preclinical data they present the fascinating activity of p-glycoprotein and its role in tumor endothelial cell chemoresistance. A promising effort in the development of anticancer drugs is the approach of targeting epigenetics of cancer. Berndsen et al. [9] examine the role of epigenetic drugs as angiostatics, as well as the application of epigenetic drugs in combination with regular angiostatic-targeted agents. The authors present an extensive literature review of various classes of epigenetic compounds, both clinically approved and experimental compounds that are paving the way to effective combination strategies. Last but not least, van Beijnum et al. [10] address the question whether microRNAs are promising candidates to successful anti-angiogenic-based treatment of cancer.

These publications all together present a broad spectrum of combinatory approaches describing opportunities for improved cancer treatment. Although many questions remain to be answered, general interest in combination strategies seems to drive the whole field of cancer research. We hope that this special issue facilitates the recognition and understanding of the power of carefully designed combination regimens.