Regulatory T (T_reg) cells play a crucial role in maintaining peripheral tolerance and preventing autoimmunity. However, they also represent a major barrier to effective antitumor immunity and immunotherapy. Consequently, there has been considerable interest in developing approaches that can selectively or preferentially target T_reg cells in tumors, while not impacting their capacity to maintain peripheral immune homeostasis. In this review, we describe our current understanding of the mechanisms underlying the recruitment, expansion, and suppressive activity of tumor‐associated T_reg cells, and discuss the approaches used and the challenges encountered in the immunotherapeutic targeting of T_reg cells. In addition, we summarize the primary clinical targets and some emerging data on exciting new potential T_reg cell‐restricted targets. We propose that discovering and understanding mechanisms that are preferentially used by T_reg cells within the tumor microenvironment will lead to strategies that selectively target T_reg cell‐mediated suppression of antitumor immunity while maintaining peripheral immune tolerance.