Human immunodeficiency virus type 1 (HIV-1) is the etiologic agent of acquired immune deficiency syndrome (AIDS). The Tat protein of HIV-1 is a potent activator of transcription directed by the viral long terminal repeat. It has been widely reported that this activation requires a specific interaction between Tat and a RNA target termed TAR in the 5'-leader sequence of HIV-1 mRNAs. In this report we present data and describe results which illustrate that under appropriate conditions activation of transcription by Tat occurs independent of the TAR element. The ability to mediate TAR-independent transactivation by Tat is constitutive in some central nervous system cells and requires prior activation in others such as T lymphocytes. Evidence implicating a specific transcription factor in mediating Tat activation is also presented. Studies with site-directed mutants demonstrate that the RNA-binding domain of Tat is dispensable for TAR-independent activation of HIV-1. In contrast, the requirement for specific components of the Tat activation domain suggests that common targets exist for this viral activation factor to exert its activity in TAR-independent and TAR-dependent transactivation pathways of HIV-1 transcriptional activation. A working model of TAR-independent transactivation, which we believe may be responsible for the activation of cellular genes which contribute to AIDS pathology, is presented.