Treg expressing the FoxP3 transcription factor has central roles to maintain peripheral tolerance and homeostasis in immune system. Treg has shown its patho-physiological roles in most of inflammatory diseases encompassing from autoimmune diseases, cancer to neurodevelopmental disorders. We analyze how they interact with other cells and microbe in healthy and disease condition, how genetic variation of FoxP3 between human individuals may influence Treg activity and influence diseases such as cancer. Recently, we elucidated how FoxP3 modulates its transcriptional program in Treg through Dichotomic protein complexes together with various interesting observations, which are still uncovered, through genetic dissection of FoxP3. Hence, we are very interested to expand previous research for uncovering molecular/cellular mechanisms to modulate FoxP3/Treg activities, developing FoxP3/Treg specific activator or inhibitor and their therapeutic application in various human inflammatory diseases.