<p>The serine/threonine kinase Akt is crucial for cell physiology and can also contribute to pathology if its activation and regulation is disturbed. This kinase phosphorylates several substrates involved in mechanisms that are altered in human disease. AKT is regulated by several post-translational modifications (PTMs), including ubiquitination/deubiquitination. Ubiquitination can both target AKT to the proteasome and promote its activation. The interplay with the deubiquitination mechanism plays a crucial role in almost all biological activities of AKT. Information on the mechanisms of AKT deubiquitination and its key players has evolved rapidly in recent years along with the development of potential targeting strategies, although many of them are still unclear. Nevertheless, AKT in turn regulates various deubiquitinases (DUBs), suggesting further targeting strategies for human diseases. In this review, we aim to provide an up-to-date overview of the dual relationship between AKT and DUBs with respect to potential translational aim.</p> Graphical Abstract <p></p>