FOXP3 is probably the best marker available currently for identifying natural regulatory T cells (T(reg)s) in mice and humans. Evidence from mouse literature suggests that natural FOXP3(+) T(reg)s are formed in the thymus and expand in the periphery to contribute significantly to peripheral T(reg)s. In this review, we discuss recent reports that show that, in humans, the formation of FOXP3(+) T(reg)s is a natural consequence of T cell activation and that de novo peripheral generation of FOXP3(+) T(reg)s is a much more dominant source of circulating T(reg)s than natural thymically derived T(reg)s. We also suggest that the role of T(reg)s in human diseases must be reviewed in light of these new findings and great caution should be exercised in immunotherapeutic interventions that involve the modulation or generation of putative T(reg)s.