Abstract: Cytokines are major controller of HIV replication and represent, at the same time, a target for viral-induced immune dysregulation. This mutual relationship has profound implications for both active HIV replication and immune-mediated governance of latency, in addition, cytokines have therapeutic value in the perspective of immune reconstitution. In the current article we will review the most relevant aspects emerged in almost 20 years of research in this area with particular reference to the distinct, but interconnected contribution of the most simple (cell lines) to the most complex (animal) models of HIV infection.