Humoral immune responses are critical for protection against immune challenge by pathogens and transformed cells, while dysregulated antibody production is a hallmark of autoimmune diseases. T follicular helper (Tfh) cells are central to the development of humoral immunity, regulating B-cell maturation, including immunoglobulin class switch recombination and somatic hypermutation, and development of memory B and antibody-producing plasma cells. These events occur as B cells migrate to and differentiate within B cell follicles of secondary lymphoid organs, with this classical program of follicular B cell maturation providing systemic immune protection. Local humoral responses are also necessary for organismal defense against immune challenge. Accordingly, T-dependent B-cell help occurs outside of B-cell follicles, including in non-lymphoid tissues such as the lung, central nervous system, joints, and kidneys. The phenotype and function of T cells that provide humoral protection against pathogens and tumors and conversely promote autoimmunity at the tissue level both overlap with and are distinct from those of canonical Tfh cells. Here, we summarize current knowledge of these tissue T-B helper cells, focusing on their differentiation and function in infection, cancer, and autoimmunity.