Due to the crucial role played by paralogous HOX13 genes on the HOX gene network organization during embryonic development, as well as in tumor progression, in this review we will discuss: (i) their physiological and pathological regulatory mechanisms during carcinogenesis; (ii) their ability to modulate tumor progression also through the interaction with co-localized ncRNAs; (iii) their potential applications as biomarkers for cancer diagnosis and treatment. This evidence concerns the gene HOXA5 and neoplasm.