Immune cells infiltrate tumors and make up a significant component of the multicellular cancer microenvironment, yet the immune system often fails to prevent tumor formation and progression. One explanation for this paradox is the presence of tolerance-promoting regulatory T cells (Tregs). Tregs were known to be essential for maintaining self-tolerance. Tregs have been found to promote tolerance to tumors in mouse models. Treg infiltration in human tumors and malignant ascites is associated with worse clinical outcomes for various types of cancers. This review focuses on the cellular and molecular mechanisms by which Tregs influence antitumor immune responses, and also discusses how these mechanisms might be exploited to develop innovative immune-based approaches that can improve cancer therapy.