In the face of systemic risk factors, certain regions of the arterial vasculature remain relatively resistant to the development of atherosclerotic lesions. The biomechanically distinct environments in these arterial geometries exert a protective influence via certain key functions of the endothelial lining; however, the mechanisms underlying the coordinated regulation of specific mechano-activated transcriptional programs leading to distinct endothelial functional phenotypes have remained elusive. Here I show that the transcription factor Kruppel-like factor 2 (KLF2) is selectively induced in endothelial cells exposed to a biomechanical stimulus characteristic of atheroprotected regions of the human carotid and that this flow-mediated increase in expression occurs via a MEK5/ERK5/MEF2 signaling pathway. Overexpression and silencing of KLF2 in the context of flow, combined with findings from genome-wide analyses of gene expression, demonstrate that the induction of KLF2 results in the orchestrated regulation of endothelial transcriptional programs controlling inflammation, thrombosis/hemostasis, vascular tone, and blood vessel development. The data also indicate that KLF2 expression globally modulates IL-1β-mediated endothelial activation. I found statins, the most widely prescribed class of cardiovascular drugs, to robustly induce endothelial expression of KLF2 and several of its transcriptional targets in a sustained manner and at pharmacologically relevant concentrations. Finally, through the development and implementation of a high throughput imaging-based screen for chemical modulators of KLF2 expression in primary endothelial cells, I identified a number of compounds that activate or suppress a KLF2 reporter. KLF2 therefore serves as a mechano-activated transcription factor important in the integration of multiple endothelial functions associated with regions of the arterial vasculature that are relatively resistant to atherogenesis. In addition, these findings implicate KLF2 in the direct vascular effects of the most widely prescribed class of cardiovascular drugs, the statins, and raise the possibility that other clinically relevant pharmacophores can be identified as modulators of this key vasoprotective gene.