Abstract In contrast to T cells that express the more prevalent αβ T cell receptor and respond to peptide antigens, T cells that express the Vγ9Vδ2T cell receptor detect and respond to non-peptide phosphorous-containing small molecules known as phosphoantigens. Because γδ T cells are early responders to infections and malignancies, it has been suggested that stimulation of their activity with small molecule phosphoantigen drugs may hold promise for therapeutic interventions. Recent studies have greatly advanced our knowledge of phosphoantigens as well as their cellular receptors. At the same time, clinical trials of phosphoantigens have suggested that development of these Vγ9Vδ2T cell agonists has met unexpected challenges. In this commentary, we summarize the biology that underlies phosphoantigen activity and discuss the structural features of synthetic phosphoantigens that affect both their ability to stimulate Vγ9Vδ2T cells and their potential as therapeutic agents.