The molecular mechanisms underlying the autoimmune disorder systemic lupus erythematosus (SLE) remain unknown. Here, Wang et. al. report that SH2 domain-containing protein tyrosine phosphatase (SHP2) activity is increased in lupus-prone MRL-lpr mouse spleen isolates and in peripheral blood mononuclear cells isolated from lupus patients. In MRL-lpr mice, SHP2 inhibition using the hydroxyindole carboxylic acid-based inhibitor 11a-1 increased life span, improved kidney function, reduced splenomegaly, diminished skin lesions, and also decreased T cell proliferation and production of SLE-associated cytokines. Moreover, 11a-1 reduced proliferation and cytokine production of cultured human lupus T cells.