Chronic reactivity of CD4 + T cells to autoantigens and to components of the commensal flora drive destructive inflammation in a variety of mouse models of autoimmunity. Insight gained using these models is empowering translational research into human disease. Immunologists are trying to assign disease culpability to one of the ever-growing number of T helper (T H) cell subsets. Although recent discovery of the interleukin 17-producing T H-17 lineage appeared to supplant the pre-eminence of T H 1 cells in promoting autoimmunity, the newest data defy simple paradigms. Here we speculate on the respective contributions to autoimmunity made by an increasingly complex list of T H subsets and argue that the T H 1 phenotype may be staging a comeback. © 2010 Nature America, Inc. All rights reserved.