Vgamma9Vdelta2 T cells, a major human peripheral gammadelta T-cell subset, react in vitro against a wide array of microbial agents and tumor cells. This broad reactivity pattern is conferred by non-peptidic phosphorylated isoprenoid pathway metabolites, referred to as phosphoantigens, which are able to specifically activate this gammadelta T-cell subset in a T-cell receptor dependent fashion. Recent studies provide new insights into the mode of action of phosphoantigens on Vgamma9Vdelta2 T cells and might explain how their recognition can allow detection of infected or altered self by the immune system. The broad antimicrobial and antitumoral reactivity of Vgamma9Vdelta2 T cells, their ability to produce inflammatory cytokines involved in protective immunity against intracellular pathogens and tumors, and their strong cytolytic and bactericidal activities suggest a direct involvement in immune control of cancers and infections. These observations have recently aided development of novel immunotherapeutic approaches aimed at Vgamma9Vdelta2 T-cell activation, which have already yielded encouraging results.