Despite an extensive knowledge of the molecular characteristics of the human immunodeficiency virus (HIV) identified more than ten years ago as the cause of AIDS (acquired immune deficiency syndrome) (Barre-Sinoussi et al. 1983) some critical questions have not been answered yet: Is the progressive disappearance of CD4+ helper T lymphocytes, the hallmark of AIDS, directly related to the killing of infected cells by the virus? If not, how do CD4+T cells die? Is HIV using its viral factory to kill uninfected bystander cells? What causes the immune system collapse in HIV infection? In the past three years some important studies have provided stimulating clues suggesting that AIDS is not only related to the killing of host cells by HIV but is also a consequence of mechanisms of misactivation of the immune system, leading to anergy or apoptosis of non-infected effector cells. We discuss some of the in vivo and in vitro models providing evidence that HIV is able to kill and cripple the immune system either by acting directly on its targets or indirectly in bystander T cells keeping in mind that HIV disease must be considered as a multifactorial process.