<p>Tissue morphogenesis and homeostasis occur at the interface of a fine coordination between cell cycle and differentiation events. The fundamental role of Hox genes during embryonic development is well established. However, less is known about their role in adult tissues and in contexts other than cellular differentiation. In this review, we focus on the role of Hox proteins in cell cycle-related events in adult tissues and highlight two main cell cycle-permissive and repressive roles for these genes. Given the significance of Hox proteins as a therapeutic target in cancer treatment, we will further discuss the existing approaches in this domain highlighting the challenges that impact the success prospects. For the successful development and application of Hox-oriented anticancer therapies, a comprehensive image of Hox roles in carcinogenic events including their mechanism of function as well as the networks/cascades within which they exert their effects is an inevitable requirement. Moreover, the functional variations of Hox genes in response to changes in the tumour microenvironment along with possible alternations of the mutational landscape in tumours during disease progression should also be taken into account as factors that might impact the therapeutic outcomes of Hox-targeting approaches.</p>