Over the past decade, there has been an accelerated understanding of immune regulatory mechanisms. Peripheral immune regulation is linked to a collection of specialized regulatory cells of the CD4(+) T cell lineage (i.e., CD4(+) Tregs). This collection consists of Tregs that are either thymically derived (i.e., natural) or peripherally induced. Tregs are important for controlling potentially autoreactive immune effectors and immunity to foreign organisms and molecules. Their importance in maintaining immune homeostasis and the overall health of an organism is clear. However, Tregs may also be involved in the pathogenesis of malignancies as now compelling evidence shows that tumors induce or recruit CD4(+) Tregs to block immune priming and antitumor effectors. Efforts are underway to develop approaches that specifically inhibit the function of tumor-associated Tregs which could lead to an increased capability of the body's immune system to respond to tumors but without off-target immune-related pathologies (i.e., autoimmune disease). In this review, the biology of human CD4(+) Tregs is discussed along with their involvement in malignancies and emerging strategies to block their function.