Immune regulation and tolerance are specific functions of the immune system, meaning at prevention or limitation of effector immune responses against inner and external insults. Regulatory T (Treg) cells are crucial players in this immune balance network. Research over the last 10 years has significantly contributed to characterizing Treg cell features, their mechanisms of function, and their role in human pathologies. The discovery of FOXP3 as an essential transcription factor not only for differentiation and function of naturally occurring Treg cells but also for regulation of intracellular molecules related to effector T-cell responses has provided new insights into the pathogenesis of immune-mediated diseases. Interestingly, there is increasing evidence that the individual signature of genes relevant for immune regulation definitely influences the final outcome of an immune response.