Homeobox genes comprise a large and essential family of developmental regulators that are vital for all aspects of growth and differentiation. Although many studies have reported their deregulated expression in cancer, few studies have established direct functional roles for homeobox genes in carcinogenesis. Nonetheless, most cases of deregulated homeobox gene expression in cancer conform to a simple rule: those that are normally expressed in undifferentiated cells are upregulated in cancer, whereas those that are normally expressed in differentiated tissues are downregulated in cancer.