Organ-on-a-Chip is a powerful technology driving physiological relevance by utilizing microfluidic techniques. The technology is expected to impact drug development and ultimately replace or reduce animal testing. Here we report a 1546 compound screen on a 3D angiogenic sprouting assay. We utilize a newly developed platform, the OrganoPlate 3-lane 64, which comprises 64 chips underneath a microtiter plate. Similar to other versions of the OrganoPlate platform, it utilizes surface tension techniques to stratify extracellular matrix gels and tissue layers, and employs passive leveling between reservoirs for inducing flow. Each chip comprises a gel lane and is flanked by two perfusion lanes. Human Umbilical Vein Endothelial Cell (HUVEC) microvessels were grown against a collagen gel according to previously reported protocols (2). The effect of a small molecule protein kinase inhibitor library of 1546 compounds was assessed on the angiogenic sprouting behavior of the vessels. The micro-vessels were exposed to an optimized cocktail of angiogenic factors in conjunction with the compound utilizing automated liquid handling. Readouts including sprouting length, number of sprouts, nuclei distance, and were acquired high content imaging (Molecular Devices, ImageXpress Micro Confocal). The screen yielded a limited number of hits that either enhanced or inhibited angiogenic capacity. The OrganoPlate 3-lane 64 showed considerable benefit over its predecessor, the OrganoPlate 3-lane 40, not only due to the increased density of chips, but also its 8-well pipette pitch for functionally similar inlets and outlets. This is the first time that Organ-on-a-Chip is reported to be utilized in a full-blown library screen, opening up the route towards early drug screening on tissue models of unrivalled physiological relevance.