Artemisinins are a set of miraculous antimalarial drugs. In addition to their potent antimalarial activities, artemisinins are found to possess some other biological properties such as cancer inhibition. The biological mechanism of artemisinin has long been controversial. However, it is generally believed that the endoperoxidic bond within artemisinin is key to its functions. The action of artemisinin is a two-step process: artemisinin first has to be activated by a reductive process to unleash the killing power of the endoperoxidic bond, and then exerts its actions. Nevertheless, the details of these processes are unclear and hotly debated. What molecules provide the necessary reduction force to activate artemisinin? Is it iron, heme or an uncertain component such as electron transport chain in the mitochondrial membrane? Evidences exist for all these possibilities, but none is conclusive. After artemisinin is activated, does it target a specific protein/biological process, or relatively non-specifically many proteins/biological processes? Does it affect vacuole or mitochondria or some other organelles? Heme/iron-mediated artemisinins activation has been widely reported and well supported by many pieces of research evidences, and almost certainly exist in many types of cells. Direct mitochondrial membrane depolarization has also been detected in Baker’s yeast and malarial parasites, but not in mammalian cells. This review is intended to summarize our current understanding of the action mechanism of artemisinin. It appears that artemisinin is associated with various biological properties, and depending on the cell types, one action might be more predominant than the others. This is further supported by the observation that the potencies of artemisinin derivatives are often not well correlated in different types of action assays. The critical issue in the future is to reveal more of the biological properties of artemisinins and pinpoint which property is more functionally relevant under a particular setting of biological action.