Arginase II has evolved from ancestral genes in early life forms. It converts L-arginine to urea and ornithine to maintain physiology. Excessive arginase II activity in mammals is associated with cardiovascular and chronic inflammation diseases. Four aspects of this elevated activity may be involved in these disease states. First, excessive arginase II activity reduces the supply of L-arginine needed by nitric oxide (NO) synthase to produce NO. Second, excessive production of ornithine leads to disrupted vascular structure and neural toxicity. Third, arginase II over-activity in certain signaling pathways leads to increased inflammation. Forth, arginase II promotes the macrophage inflammatory response (M1 macrophage). Here, we review the role of arginase II in cardiovascular diseases and macrophages and in oxidative stress and inflammation mechanisms. We also discuss targeting arginase II as a promising therapeutic strategy.