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Background: Teleostfish, including zebrafish, are able to regenerate heart, retina, spinal cord, and fins after a lesion. The tie2-eGFP zebrafish is a suitable model to study the whole vascular tree down to the capillary level. Therefore, we introduced a novel assay to quantify angiogenesis after partial amputation of the zebrafish caudal fin. Methods: At first, the zebrafish caudal fin was partially amputated. Complete regeneration of the vasculature and the fin itself occurred within five weeks at 30°C. Remarkably, initial size and shape of the fin as well as the vascular parameters and patterns were completely restored. Most importantly, the concept of a reference situation was therefore introduced. Alterations in the neo-angiogenesis induced by external manipulations (pharmaceutical compounds, growth factors, flow disturbance etc.) can be precisely observed and quantified using stereomicroscopic imaging. Because blood vessels run straight and planar at the site of interest, the zebrafish caudal fin is introduced as a 2D-model. Three main quantitative parameters were introduced in this angiogenic assay. First, the total area (TA) represents the area of the fin that regenerated after partial amputation. Second, the vascular projection area (VPA) represents the regenerated vascular area visualized by a stereomicroscope. Third, the contour length (CL) represents the length of the blood vessel wall visualized by a stereomicroscope. During the first seven days of regeneration, extensive angiogenic growth was observed. Therefore, we introduced the short angiogenic assay. It allows evaluation of pro- and anti-angiogenic compounds within a week using unbiased stereological methods. In addition, this novel angiogenic assay includes a multitude of investigations in parallel. By the use of confocal imaging and transmission electron microscopy, morphology is linked to observed alterations in vivo. Hemodynamic conditions and their role in the process of neo-angiogenesis are evaluated. Moreover, the interplay between the two most important modes of angiogenesis (sprouting and intussusceptive angiogenesis) is evaluated. Conclusions: The zebrafish caudal fin regeneration assay is a promising and highly reproducible model for time-efficient quantitative evaluation of angiogenesis. It is useful to assess neo-angiogenic mechanisms and the effects of different pro-and anti-angiogenic treatments. The model has potential implications on future treatment strategies of angiogenesis related diseases such as carcinogenesis, retinopathy, macular degeneration, and wound healing, among others. [ABSTRACT FROM AUTHOR]