HOX transcription factors regulate basic and cell type-specific activities throughout life. The combinatorial patterns of HOX gene expression along anterior-posterior and proximal-distal axes are relatively tightly-defined during embryogenesis and key remnants of such positional memory persist through adulthood. These normal patterns of HOX gene expression can be compared to a growing body of work on their dysregulation during carcinogenesis. In this review, simple and complex changes in HOX gene expression patterns will be considered using examples from hematopoietic, breast and lung cancers. Changes in individual and combinatorial patterns of HOX gene expression, co-factor expression and chromatin structure will be considered in a discussion of potential roles for dysregulated HOX genes in target gene regulation and various aspects of cancer progression. Collectively, studies indicate that, although a variety of factors must be delineated to assess the roles of individual HOX genes in particular cancers, approaches that modulate HOX gene expression and monitor both changes in the regulation of key target genes and cellular activities are making the greatest initial advances in this assessment.