CD4⁺ Foxp3⁺ regulatory T cells (Tregs) represent a major cellular mechanism in tumor immune evasion. Elimination of Treg activity has become a strategy to devise an effective tumor immunotherapy. We reported that TNF receptor type II (TNFR2), one of two receptors transducing TNF biological activity, is preferentially expressed by the most suppressive subset of Tregs. By interaction with TNFR2, TNF plays a decisive role in the activation, expansion and phenotype stability of Tregs. We also found that highly suppressive TNFR2-expressing Tregs appear to be tumor-associated Tregs. This finding has been supported by recent studies in mouse tumor models and in cancer patients. In this chapter, published data revealing the important role of TNFR2⁺ Tregs in tumor development and metastasis in different tumor types are reviewed and analyzed. The therapeutic potential of targeting TNF-TNFR2 interaction as means to eliminate Treg activity, and consequently to enhance anti-tumor immune responses, also is discussed.