The Hox clustered organization is fundamental for the precise regulation and the function of each gene and hence for the correct formation of the embryo. Analysis of Hox mutant mice endorses the collinear relationship between the position of individual genes within Hox clusters and the structural defects observed along the anterior-posterior axis. While the developmental role of Hox genes is well established, the regulation of Hox gene expression in the embryo remains incompletely understood. A complex array of different modes of regulation governs the precise Hox expression. Regulation primarily occurs at the transcriptional level via the combinatorial interplay of several signaling pathways and transcriptional factors that interact with positive and negative cis-acting sequences to differentially control Hox expression in a spatio-temporal and tissue-specific fashion. The proximity of Hox genes in clusters implies the integrated regulation of adjacent Hox promoters through the sharing, the competition and/or the selective use of defined enhancers. In parallel, global regulatory elements located outside the Hox clusters and able of long-distance action coordinate the expression of several genes along the Hox complexes. Large-scale chromatin remodeling events also participate to the regulation of the collinear expression of Hox genes. Transcriptional regulators of Hox gene expression have been identified. They include developmentally regulated factors like the CDX homeodomain-containing proteins that integrate retinoic acid, FGF and Wnt signaling for the setting of the correct expression domain of Hox genes. Hox genes are also directly responsive to RA, which activates retinoic acid receptors that then interact with retinoic acid Formestane response elements identified near Hox genes mainly from paralog groups 1 to 5. Hox expression is under the control of HOX proteins themselves involved in auto- and cross-regulation. Lubiprostone Finally, ubiquitously expressed transcription factors such as the multifunctional Yin Yang 1 protein can modulate Hox expression in specific contexts.