The hypothesis of the existence of T cells specialized in dampening immunity was put forward in the 1970s. However, failure to identify a specific molecular marker hampered the isolation and unequivocal characterization of such cells for two decades. In the early 1990s, it became clear that a small subset of CD25hi CD4 T cells, generated in the neonatal thymus and naturally occurring in the mature immune system throughout life, played a key role in controlling autoimmunity in various experimental models. Soon thereafter, their human counterparts were characterized using the same cell surface marker combination in conjunction with functional assays in vitro. A rare X-linked autoimmune syndrome made it possible to unequivocally assign a molecular identity to regulatory T cells (Tregs). Indeed, this inherited disorder results from inactivation of the forkhead–winged-helix transcription factor, Foxp3, which causes the lymphoproliferation and multiorgan autoimmunity found in scurfy mutant mice and/or in humans with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome. Foxp3 has been shown to be the molecular factor necessary to establish Treg lineage specification and functional competence. It is currently the most specific marker for identifying regulatory T cells by immunohistochemistry or flow cytometry or in vivo in genetically engineered reporter mice. Tregs have taken center stage in immunological research. Initially thought to be mainly responsible for the maintenance of self-tolerance, including oral and feto-maternal tolerance, their range of action has been extended to immunity against pathogens, allergy and asthma. Moreover, their immunosuppressive potential has been explored in organ transplantation – both in experimental and clinical settings - and much attention and effort have been devoted to dissecting their involvement in tumor immunity. Much to our surprise, Tregs have recently been shown to play an important role outside of the classical realm of the immune system, namely, in fat metabolism and insulin resistance, and more “exotic” functions may be yet to come. As far as their mode of suppression is concerned, we recently learned that Tregs seem to reciprocally adapt to the T effector subclass (i.e., Th1, Th2 or Th17 cells) they suppress in the local microenvironment. This reflects an unanticipated degree of target specificity and sophistication of this Treg lineage. Notwithstanding all these exciting new developments, in the special section in this issue three articles bring us up-to-date on the role of Treg in tumor immunity. Zou et al. present a concise summary of numerous studies on the infiltration of a variety of human tumors by Treg and the prognostic significance of their intra-tumoral presence. Remarkably, a significant degree of enrichment of Treg can correlate with a better or worse prognosis and this outcome seems to depend on the tumor type. Intuitively, a high number of Treg in tumors should result in dampened local tumor immunity and, hence, a less favorable prognosis, and this is indeed observed in many cases. The opposite outcome is thought to result from a reduction in the local inflammatory response by Treg. Chronic inflammation is regarded as a strong promoter of tumorigenesis. Why the balance in any particular case tilts to one or the other side is not clear at present. Nishikawa and Sakaguchi summarize various potential strategies to deplete Treg in tumor patients in vivo based on the notion that Treg can impede effective anti-tumor responses by the innate and adaptive immune system. They go through a series of potential markers enriched in, but not exclusively specific for, Tregs. Indeed, the fact that most of these markers are also expressed on activated T cells obviously limits the precision of this approach. Treatment with an anti-CTLA-4 mAb has so far yielded the most convincing clinical results, a long-awaited reassurance that immunotherapy of tumors holds future promise. Erdman and Poutahidis elaborate on the aforementioned role of chronic inflammation in promoting tumor development, the best example being the causative role of Helicobacter p. infection in gastric cancer. They argue that exposure to pathogens in early life is necessary to properly establish the Treg compartment, which then is able to curb exuberant chronic inflammatory responses as seen in inflammatory bowel disease (IBD) and supposedly in cancer. Modern hygiene, however, has considerably reduced exposure to environmental antigenic challenge and thus might also influence the establishment of a protective Treg pool. This idea – known as the hygiene hypothesis – has also been invoked to explain the rising number of allergies observed among the population of affluent western societies. Indeed, accumulating epidemiologic evidence suggests that modern western life style leads to higher rates of certain cancer types. The authors also advocate a remedy for this situation, namely, the controlled exposure to antigenic stimuli, e.g., by including probiotics in the diet.