Summary: CD4+ T cells are central regulators of both humoral and cellular immune responses. There are many subsets of CD4+ T cells, the most prominent being T-helper 1 (Th1), Th2, Th-17, and regulatory T cells, specialized in regulating different aspects of immunity. Without participation by these CD4+ T-cell subsets, B cells cannot undergo isotype switching to generate high-affinity antibodies, the microbicidal activity of macrophages is reduced, the efficiency of CD8+ T-cell responses and CD8+ T-cell memory are compromised, and downregulation of effector responses is impaired. It therefore stands to reason that memory CD4+ T cells are likely to fulfill an important facilitator role in the maintenance and control of protective immune responses. This review discusses some issues of importance for the generation of memory CD4+ T cells and focuses in particular on their heterogeneity and plasticity, with respect to both phenotypic characteristics and function. Finally, we discuss a number of factors that affect long-term maintenance of memory CD4+ T cells.