The Hox gene family occupies a central position in the control of body patterning by regulating the transcription of downstream effectors that, in turn, direct the morphogenetic events leading to the complex body forms along the axes. Analysis of Hox mutant mouse lines has revealed a panoply of phenotypes indicative of the broad range of Hox genes action throughout embryonic and postnatal life. Although Hox genes have been the subject of extensive research in the last two decades, the comprehension of the mechanisms involved in their regulation and function still remains elusive. Here, we present an overview of our current knowledge about one Hox gene family member, Hoxa5. The phenotypic survey of Hoxa5 mutant mice has unveiled the crucial role of this gene in regulating morphogenesis and specifying regional identity along the embryo. A majority of Hoxa5 mutant pups die at birth from defective respiratory tract. Surviving mutants present deficient alveolar septation revealing the importance of Hoxa5 during formation and maturation of the lung. Hoxa5 also participates in the morphogenesis of the digestive tract as well as that of the thyroid and mammary glands. Hoxa5 expression is restricted to the mesenchyme, and its action appears to be mediated through the control of mesenchymal-epithelial interactions during organogenesis. The implication of Hoxa5 in tumorigenesis has also been documented. In breast cancer, Hoxa5 down-regulation may impact on p53 gene expression, contributing to the oncogenic process. In contrast, the loss of Hoxa5 function limits leukaemia associated with specific chromosomal translocations. Thus, inappropriate Hoxa5 gene expression may disrupt normal growth and differentiation programs causing neoplasia. Hox gene function is intimately linked to its correct expression. Regulation of Hoxa5 expression requires multiple cis-acting regions, some encompassing coding sequences from neighboring genes. Moreover, it is complicated by the presence of several transcription units. Together these data enlighten the importance of Hox cluster organization in Hoxa5 function.