Summary: Our understanding of the importance of CD4+ T cells in orchestrating immune responses has grown dramatically over the past decade. This lymphocyte family consists of diverse subsets ranging from interferon-γ (IFN-γ)-producing T-helper 1 (Th1) cells to transforming growth factor-β (TGF-β)-secreting T-regulatory cells, which have opposite roles in modulating immune responses to pathogens, tumor cells, and self-antigens. This review briefly addresses the various T-cell subsets within the CD4+ T-cell family and discusses recent research efforts aimed at elucidating the nature of the ‘T-cell help’ that has been shown to be essential for optimal immune function. Particular attention is paid to the role of Th cells in tumor immunotherapy. We review some of our own work in the field describing how CD4+ Th cells can enhance anti-tumor cytotoxic T-lymphocyte (CTL) responses by enhancing clonal expansion at the tumor site, preventing activation-induced cell death and functioning as antigen-presenting cells for CTLs to preferentially generate immune memory cells. These unconventional roles for Th lymphocytes, which require direct cell-to-cell communication with CTLs, are clear examples of how versatile these immunoregulatory cells are.