In this study we have identified the target genes of SREBP-1a and SREBP-1c in primary cultures of human skeletal muscle cells using adenoviral vectors expressing the mature nuclear form of human SREBP-1a or SREBP-1c combined with oligonucleotide microarrays. Overexpression of SREBP-1a led to significant changes in the expression of 1,315 genes (655 up- and 660 down-regulated), whereas overexpression of SREBP-1c modified the mRNA level of 514 genes (310 up- and 204 down-regulated). Gene ontology analysis indicated that in the human muscle cells, SREBP-1a and 1c are involved in the regulation of a large number of genes that are at the crossroads of different functional pathways, of which, several are not directly connected with cholesterol and lipid metabolism. 652 of all genes identified to be differentially regulated upon SREBP overexpression had a SRE motif in their promoter sequences. Among these, 429 were specifically regulated by SREBP-1a, 69 by SREBP-1c, and 154 were regulated by both 1a and 1c. As both isoforms recognize the same binding motif, we determined if some of these functional differences could depend on the environment of the SRE motifs in the promoters. Results from promoter analysis showed that different combinations of transcription factor binding sites around the SRE binding motifs may determine regulatory networks of transcription that could explain the superposition of the lipid and cholesterol metabolism with various other pathways involved in adaptive responses to stress like hypoxia and heat shock, or involvement in the immune response.