Studies with mouse models have established the pathogenic roles of T follicular helper (Tfh) cells in antibody-mediated autoimmune diseases. In contrast, evidence in human autoimmune pathogenesis has been lacking for years. Recent progress in understanding on the biology of human Tfh cells and on the approaches assessing their response has enabled gaining insights into the alterations of Tfh response and the underlying mechanisms. For example, increase of circulating Tfh (cTfh) cells expressing PD-1 and/or ICOS and alterations in the composition of cTfh subsets have emerged as a common feature in a broad range of autoimmune diseases. Defining the differentiation mechanism and the mode of actions of Tfh cells in inflamed lymphoid organs and tissues in patients will facilitate developing novel treatment strategies targeting Tfh cells in autoimmune diseases.