We have used lacZ reporter gene constructs to study the cis regulation of the murine Hoxd-11 gene (previously Hox-4.6) in transgenic mice. We identified a genomic region, which was able to simulate important aspects of the developmental regulation of the gene. A short regulatory region, located 3' to the Hoxd-11 transcription unit, was required to mimic initial activation. This regulatory region contains two stretches of DNA, that are highly conserved in the chicken Hoxd-11 3' flanking region. A chimeric construct containing these short homologous regions from the chicken gene could replace the complete murine fragment thus demonstrating that the conserved domains carry the main regulatory elements involved in this activation. The first half of this bipartite regulatory region has positive regulatory activity, while the second half is required to restrict gene expression to the proper posterior domain in the somitic mesoderm. Our results suggest that the control of the Hoxd-11 promoter involves tissue-specific cooperations between regulatory elements.