The human retinoblastoma gene product appears to play an important role in the negative regulation of cell proliferation. Functional inactivation of Rb can be mediated either through mutation or as a consequence of interaction with DNA tumor virus encoded proteins. Of all the Rb associations described to date, the identification of a complex between Rb and the transcription factor E2F most directly implicates Rb in regulation of cell proliferation. E2F was originally identified through its role in transcriptional activation of the adenovirus E2 promoter. Sequences homologous to the E2F binding site have been found upstream of a number of genes that encode proteins with putative functions in the G1 and S phases of the cell cycle. E2F-1 is a member of a broader family of transcriptional regulators including E2F-2, E2F-3, E2F-4, E2F-5 and E2F-6, each of which forms heterodimers with a second protein, DP-1, forming an “active” E2F transcriptional regulatory complex.