It is generally believed that the role of CD4⁺ T cells is to coordinate the different arms of the adaptive immune system to shape an effective response against a pathogen and regulate nonessential or deleterious activities. However, a growing body of evidence suggests that effector CD4⁺ T cells can directly display potent antiviral activity themselves. The presence of cytolytic CD4⁺ T cells has been demonstrated in the immune response to numerous viral infections in both humans and in animal models and it is likely that they play a critical role in the control of viral replication in vivo. This article describes the current research on virus-specific cytolytic CD4⁺ T cells, with a focus on HIV-1 infection and the implications that this immune response has for vaccine design.