Envelope-based immunogens capable of generating high titers of neutralizing antibodies have until now been difficult to generate, or failed to act as useful vaccines to prevent HIV-1 infection and disease progression. On the other hand, humoral immune responses to self and allogeneic cellular antigens involved in HIV-1 docking and entry are present both in infected patients and in subjects with natural resistance to HIV-1 infection, where they share similarities but also display definite differences. By dissecting these subtle differences, crucial cellular and molecular markers, possibly correlated with natural resistance to HIV-1 and with the modulation of clinical progression in stably infected patients, have been identified. Here, state-of-the art knowledge on anti-self immune responses following infection or exposure to HIV will be reviewed. The possible implications of these mechanisms in the design of unconventional therapies aimed to counteract the peculiar HIV-1 capability to circumvent the immune system will be discussed.