There has been renewed interest in the superantigens as antitumor agents with the discovery of a group of bacterial superantigens known as the enterotoxin gene cluster (egc staphylococcal enterotoxins [SEs]). This article discusses the mechanisms by which egc SEs induce tumor killing and pleurodesis. The application of SE homolog and nucleic acid compositions as vaccines and for treatment of established tumors is reviewed. Finally, the use of native SEs ex vivo-intratumorally and intravesicularly administered superantigens against established tumors-is described and the interrelation between superantigen therapy and chemoradiotherapy.