Sterol regulatory element-binding proteins (SREBPs) activate promoters for key genes of metabolism to keep pace with the cellular demand for lipids. In each SREBP-regulated promoter, at least one ubiquitous co-regulatory factor that binds to a neighboring recognition site is also required for efficient gene induction. Some of these putative co-regulatory proteins are members of transcription factor families that all bind to the same DNA sequence elements in vitro and are often expressed in the same cells. These two observations have made it difficult to assign specific and redundant functions to the unique members of a specific gene family. We have used the chromatin immunoprecipitation (ChIP) technique coupled with a transient complementation assay in Drosophila SL2 cells to directly compare the ability of two members of the CREB/ATF family to function as co-regulatory proteins for SREBP-dependent activation of the HMG-CoA reductase promoter. Results from both of these experimental systems demonstrate that CREB is an efficient SREBP co-regulator but ATF-2 is not.