Much attention has been focused on CD4+ memory / primed T cells and monocytes / macrophages as the predominant targets of HIV infection. Considerable evidence, however, indicates that cell types that are classically not permissive to HIV infection, can be a potent source of productive virus replication in response to immune modulation. This immune modulation can be in the form of cytokine stimulation pre- or postinfection or by activating these “non-conventional” targets. In this review, we will provide evidence for immune modulation of HIV infection with special emphasis on immune modulation of HIV replication in classically non-HIV permissive primary cells of both lymphoid and non-lymphoid origins. We will also examine the impact of HIV infection of these non-conventional targets as they pertain to both HIV immunoand neuro-pathogenesis.