The adaptive effector CD4⁺ T helper-mediated immune response is highly heterogeneous, based on the development of distinct subsets that are characterized by the expression of different profiles of cell surface markers. Functional impairment of T cells is characteristic of many chronic mouse and human viral infections. Excessive induction of apoptosis in infected and uninfected CD4⁺ T cells has been proposed as one of the pathogenic mechanisms that may impair the immune response and cause the development of acquired immune deficiency syndrome (AIDS). Thus, the death of effector/memory CD4⁺ T cells during both the acute and chronic phase represents one the main characteristic of such viral infection that predicts disease outcome. Improving our understanding of the molecular mechanisms leading to the death of memory CD4⁺ T cells should enable us to improve vaccination protocols and treatments, by combining them with antiretroviral drugs and molecules designed to decrease apoptotic phenomena.