Many studies have demonstrated that HIV-1 Tat plays a pivotal role both in the HIV-1 replication cycle and in the pathogenesis of HIV-1 infection. Indeed, Tat affects the HIV-1 replication cycle regulation increasing the proviral transcription rate several hundred-fold and acting on the elongation of viral transcripts. Moreover, Tat displays several important biological activities committed to uninfected and infected cells by a paracrine/autocrine mechanism due to secretion of Tat from infected cells. In particular, Tat modulates the expression of several cellular genes and triggers the activation of some signal transduction pathways and transcription factors suggesting a complex role in the scenario of HIV-1 infection. This review focuses on some aspects of Tat biological activity with particular regard to effects of Tat on cell proliferation and survival regulation.