Coined in the late eighties, the term “angiogenic switch” refers to a time-restricted event during tumor progression where the balance between pro- and anti-angiogenic factors tilts towards a pro-angiogenic outcome, resulting in the transition from dormant avascularized hyperplasia to outgrowing vascularized tumor and eventually to malignant tumor progression. The molecular players and mechanisms underlying the angiogenic switch have been intensely investigated. In particular, a large number of pro-angiogenic factors and angiogenic inhibitors activated and repressed, respectively, in their activities during the angiogenic switch have been identified and characterized. Part of this research has lead to the development of various pro- and anti-angiogenic therapies that are currently tested in clinical trials or are already in clinical use. More recently, transgenic mouse models of cancer have been instrumental in revealing that inflammatory responses within the tumor microenvironment are critically contributing to the onset of tumor angiogenesis. These mouse models closely recapitulate multistage carcinogenesis in cancer patients and represent reliable tools to study the molecular and cellular players implicated in the onset and maintenance of tumor angiogenesis. Furthermore, they also offer the opportunity to assess the efficacy of novel anti-angiogenic cancer therapies and the nature of developing resistance mechanisms. These experiments have provided first important concepts to improve anti-angiogenic therapy and thus directly contribute to their translation to the clinical setting.