The transcription factor STAT4 has been implicated in the pathogenesis of autoimmune diseases, including inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and diabetes mellitus. Here, we report p-biaryl phosphates and phosphonates as the first small-molecule inhibitors of STAT4. The most potent p-biaryl phosphate inhibited the protein-protein interaction domain of STAT4, the SH2 domain, with submicromolar potency (K(i) = 0.35 microM) and 14-fold selectivity over the closely related family member STAT3, which has the same core peptide binding motif as STAT4. Further development resulted in the phosphatase-stable inhibitor Stafori-1, which protected STAT4 but not STAT3, against thermal denaturation in cell lysates. Its cell-permeable prodrug Pomstafori-1 selectively inhibited STAT4 phosphorylation in cultured human cells at low micromolar concentrations. Our data open up the possibility of exploring STAT4 as a target protein for small molecules in the treatment of unmet medical needs.