Human immunodeficiency virus-1 (HIV-1) is usually transmitted through sexual contact and in the very early stages of infection establishes a persistent infection in lymphatic tissues (LT). Virus is produced and stored at this site in a dynamic process that slowly depletes the immune system of CD4+ T cells, setting the stage for AIDS. In this review, I describe the changes in viral and CD4+ T cell populations in LT over the course of infection and after treatment. I present recent evidence that productively infected CD4+ T cells play an important role in establishing persistent infection from the onset, and that the LT are the major reservoir where virus is produced and stored on follicular dendritic cells (FDCs). I discuss the methods used to define the size of viral and CD4+ T cell populations in LT and the nature of virus-host cell interactions in vivo. These experimental approaches have identified populations of latently and chronically infected cells in which virus can elude host defenses, perpetuate infection, and escape eradication by highly active antiretroviral treatment (HAART). I discuss the dramatic impact of HAART on suppressing virus production, reducing the pool of stored virus, and restoring CD4+ T cell populations. I discuss the contributions of thymopoiesis and other renewal mechanisms, lymphatic homeostasis and trafficking to these changes in CD4+ T cell populations in LT, and conclude with a model of immune depletion and repopulation based on the limited regenerative capacity of the adult and the uncompensated losses of productively infected cells that treatment stems. The prediction of this model is that immune regeneration will be slow, variable, and partial. It is nonetheless encouraging to know that even in late stages of infection, control of active replication of HIV-1 provides an opportunity for the immune system to recover from the injuries inflicted by infection.