Human Vγ2Vδ2T cells recognize nonpeptide antigens derived from microbial pathogens in a TCR-dependent manner, such as isopentenyl pyrophosphate-related metabolites and alkyl amines. Recent crystallographic analysis of the γ2VδTCR along with the site-directed mutagenesis studies has strongly suggested that theγ2VδTCR directly interacts with nonpeptide antigens via a positively-charged pocket formed by CDR2 and CDR3 regions. Full activation ofγ2VδT cells by nonpeptide antigens leading to proliferation and cytokine production was suggested to require cognate cellular interaction with the cells displaying the antigens via specific adhesion molecules. Synthetic nitrogen-containing bisphosphonate compounds such as pamidronate were also shown to activate the same subset ofγ2VδT cells in a TCR-dependent manner. Most notably, these compounds can efficiently sensitize a wide spectrum of human tumor cells to the lysis byγ2VδT cells. These characteristics ofγ2VδT cells confer them a unique role in cross-immunity in infection and malignancy, and may provide a novel strategy for immunotherapy of human cancer.