The MOF (males absent on the first)-containing NSL (non-specific lethal) complex binds to a subset of active promoters in Drosophila melanogaster and is thought to contribute to proper gene expression. The determinants that target NSL to specific pro- moters and the circumstances in which the complex engages in regulating transcription are currently unknown. Here, we show that the NSL complex pri- marily targets active promoters and in particular housekeeping genes, at which it colocalizes with the chromatin remodeler NURF (nucleosome remodeling factor) and the histone methyltransferase Trithorax. However, only a subset of housekeeping genes associated with NSL are actually activated by it. Our analyses reveal that these NSL-activated pro- moters are depleted of certain insulator binding pro- teins and are enriched for the core promoter motif ‘Ohler 5’. Based on these results, it is possible to predict whether the NSL complex is likely to regulate a particular promoter. We conclude that the regula- tory capacity of the NSL complex is highly context- dependent. Activation by the NSL complex requires a particular promoter architecture defined by com- binations of chromatin regulators and core promoter motifs.