Suppressor/regulatory T cells were first shown to have an impact on cancer progression in experimental tumor models during the 1970s. However, the lack of specific markers hindered mechanistic investigations, and skepticism grew in the scientific community due to variability in cell populations and reported functions. The identification of regulatory CD4⁺CD25⁺ T cells has generated a great deal of renewed interest in cells that have immune regulatory properties. This article will provide a brief historical review of suppressor T cells and cancer, experimental and clinical evidence that CD4⁺CD25⁺ natural regulatory T cells play a role in cancer progression, and briefly discuss current strategies to inhibit these cells in an effort to enhance cancer immunotherapy.