For years our group has sought to identify and characterise a safer alternative to glucocorticoids (“steroids”) for treatment of patients with autoimmune diseases, particularly systemic lupus erythematosus (SLE). GILZ has emerged as a strong candidate, with important roles in regulating activation and effector function in multiple types of immune cells. In mouse and human, loss of GILZ permits the development of B cell-mediated autoimmunity, and GILZ expression is associated with the suppression of master regulators of B cell differentiation. We have discovered similar regulatory roles for GILZ in setting thresholds for activation in CD4 and CD8 T cells, keeping in check cellular immune responses. Moreover, GILZ is an essential negative regulator of innate immune pathways including inflammatory cytokine secretion in response to TLR ligation, and type I interferon production, which is a key driver of pathogenesis in SLE. Because of its many broad and specific anti-inflammatory functions, our work has established GILZ as a key regulator of immune responses and a leading candidate in the search for new therapeutic strategies to achieve disease control in autoimmunity.