Immunostimulatory members of the tumor necrosis factor (TNF) superfamily (TNFSF) of ligands are known to be important regulators of the immune system. These trimeric molecules interact with members of the TNF receptor superfamily (TNFRSF) to stimulate immune cells. Of the TNFSF molecules, CD40 ligand (CD40L, also called CD154 or TNFSF5) is the most crucial molecule for activating antigen-presenting cells (APCs) and thereby initiating the immune response. Evidence has accrued indicating that HIV infection either selectively depletes those CD4(+) T cells that express CD40L in response to antigen or down-regulates CD40L expression by these cells. Because CD40L expression is necessary for the immune defense against HIV and opportunistic infections, an insufficiency of CD40L could contribute to the progression of AIDS. CD40L contributes to the antiviral mechanisms of the host by inducing anti-HIV beta-chemokines and activating CD8(+) T cells. However, CD40L stimulation can lead to enhanced HIV replication under certain experimental conditions, due to its immune activating properties and the need for cellular activation for high-level HIV production. On balance, it is believed that reversing the relative CD40L deficiency seen in HIV infection will be important for immune restoration in AIDS. In addition, adding CD40L to a therapeutic or preventative vaccine could lead to strengthened antiviral immunity. Because of the complexities in delivering this molecule, a number of forms of CD40L have been developed, and one form of soluble CD40L has been tested in humans. New strategies are being developed to translate the profoundly immunostimulatory effects of CD40L found in animal models to humans with HIV infection.