Significant gaps remain in the understanding of how blood cells and the vasculature differentially support coagulation enzyme complex function leading to regulated thrombus formation in vivo. While studies employing knock-out or transgenic mice have proved useful many of these scientific gaps partly result from the lack of molecular approaches and analytic tools with appropriate sensitivity for incisive conclusions. Over the past decade, studies employing state of the art videomicroscopy to image hemostasis in vivo following laser injury to the mouse cremaster arteriole have begun to bridge these gaps and provide remarkable insight into the early events of the hemostatic process. Many of these new insights have started to question some of the long-standing concepts that were driven by in vitro approaches. This review provides an overview of this technology, describes insights that have been made using it, and discuss limitations and future directions.