With the advent of the concept of dominant tolerance and the subsequent discovery of CD4⁺ regulatory T cells expressing the transcription factor FOXP3 (Tregs), almost all productive as well as nonproductive immune responses can be compartmentalized to a binary of immune effector T cells and immune regulatory Treg populations. A beneficial immune response warrants the timely regulation by Tregs, whereas a nonproductive immune response indicates insufficient effector functions or an outright failure of tolerance. There are ample reports supporting role of Tregs in suppressing spontaneous auto-immune diseases as well as promoting immune evasion by cancers. To top up their importance, several non-immune functions like tissue homeostasis and regeneration are also being attributed to Tregs. Hence, after being in the center stage of basic and translational immunological research, Tregs are making the next jump towards clinical studies. Therefore, newer small molecules, biologics as well as adoptive cell therapy (ACT) approaches are being tested to augment or undermine Treg responses in the context of autoimmunity and cancer. In this brief review, we present the strategies to modulate Tregs towards a favorable clinical outcome.