Interleukin 16 was the first described T cell chemoattractant. Since its initial report in 1982 work from a variety of groups have more fully characterized IL-16 as a highly conserved pro-inflammatory cytokine, distinct from the chemokine family, which through direct interaction with CD4, functions to recruit and partially activate specifically CD4+ immune cell populations at sites of inflammation. The effects on CD4+ T cells also includes induction of IL-2 receptors enabling IL-2 facilitated T cell proliferation. Most recently IL-16 stimulation has been found to inhibit HIV-1 viral replication. This review on IL-16 addresses the structure-function relationship of IL-16 with its receptor CD4; its role in inflammation and HIV-1 infection; and discusses potential therapeutic modalities for IL-16 in inflammation and for immune reconstitution in HIV-1 infection.