Upstream stimulating factors, USF-1 and -2, are members of the evolutionary conserved basic-Helix-Loop-Helix-Leucine Zipper transcription factor family. The ubiquitously expressed USF-1 and -2 proteins of respectively 43 kDa and 44 kDa interact with high affinity to cognate E-box regulatory elements (CANNTG) which are particularly represented over the genome. The USF transcription factors are key regulatory elements of the transcriptional machinery mediating recruitment of chromatin remodelling enzymes, interacting with co-activators and members of the pre-initiation complex (PIC). Furthermore, transcriptionnal activity and DNA-binding of the USF proteins can be modulated by multiple ways including phosphorylation by distinct kinases (p38, protein kinase A and C, cdk1 and PI3Kinase), homo or heterodimerization formation and DNA modification of the E-box binding motif (methylation, SNP). Taken together, these parameters render very complex the understanding of the USF-dependent gene expression regulation. USF transcription factors have thus been involved as key regulators of a wide number of gene regulation network including stress and immune response, cell cycle and proliferation. This review will thus focus on general aspect of the USF transcription factors and their implications in some regulatory networks.