Generation of memory T cells, which mediate immunity against microbes and cancers, relies, for optimal activity, on the interactions of multiple cell types that are highly regulated through the expression of soluble factors and negative and positive receptors. Their disruption will lead to aberrant immune responses, which can result in the invasion of the host by foreign pathogens. In chronic viral infections including HIV and hepatitis C virus, persistence of antigen and lack of CD4 help (HIV) disrupt memory T-cell function and induce defects in memory T-cell responses, which have been defined as T-cell exhaustion. In this review, we examine the molecular mechanisms involved in such T-cell dysfunction. Better understanding of these mechanisms will assist in the development of novel therapies to prevent the immune damage mediated by HIV infection.