Increasing evidence supports the existence of elevated numbers of regulatory T cells (T(reg) cells) in solid tumors and hematologic malignancies. Whereas the biology of CD4(+)CD25(+)FOXP3(+) T(reg) cells in murine models seems to be rather straightforward, studies in human diseases are more difficult to interpret due to expression of CD25 on activated effector T cells as well as T(reg) cells. More importantly, early studies in human tumors were mainly focused on CD4(+)CD25(+) T(reg) cells lacking interrogation of more specific markers such as FOXP3 expression. Although the increase of T(reg) cells seems to be a characteristic feature in most tumors, little is known about the molecular and cellular mechanisms responsible for the increase and maintenance of elevated levels of T(reg) cells in cancer. We will discuss earlier data in the context of recent findings in T(reg)-cell biology with a particular emphasis on CD4(+)CD25(high)FOXP3(+) T(reg) cells in human malignancies.