Specialized subpopulations of CD4⁺ T cells survey major histocompatibility complex class II–peptide complexes to control phagosomal infections, help B cells, regulate tissue homeostasis and repair or perform immune regulation. Memory CD4⁺ T cells are positioned throughout the body and not only protect the tissues from reinfection and cancer, but also participate in allergy, autoimmunity, graft rejection and chronic inflammation. Here we provide updates on our understanding of the longevity, functional heterogeneity, differentiation, plasticity, migration and human immunodeficiency virus reservoirs as well as key technological advances that are facilitating the characterization of memory CD4⁺ T cell biology.