Accumulating evidence indicates that regulatory T cells (Treg) are a distinct group of immune cells that are essential in maintaining immunologic homeostasis, largely by their ability to suppress responses mediated by other populations of immune cells. In a microbial infection, this suppressive function can be temporally overridden via different mechanisms so that the immune system can mount efficient antimicrobial immunity. However, if Tregs suppressive function is not restored after the elimination of pathogens, the resulting immune hyperactivity would injure self tissues and autoimmune diseases may occur. In case of cancer, the overexpressed self-antigens can induce tumor/self-specific Treg cells that suppress effective antitumor responses. A wealth of evidence clearly shows that some microbes and their products, such as CpG-ODN, OK-432 and BCG, are effective in cancer treatment, most likely by suppression of Tregs function. Therefore, the search for approaches which can override Tregs suppressive functions and trigger an efficient antitumor immunity is crucial to the development of effective cancer immunotherapy.