Ubiquitylation is a crucial post-translational protein modification that regulates several cellular processes in eukaryotes, including inflammatory responses, endocytic trafficking and the cell cycle. Importantly, ubiquitylation also has a central role in modulating eukaryotic defence systems; however, accumulating evidence shows that many bacterial pathogens exploit host ubiquitin systems for their own benefit. In this Review, we highlight the ways in which human bacterial pathogens target ubiquitylation to subvert and manipulate host defence systems, with a focus on the role of molecular mimicry and secreted bacterial effector proteins. These strategies enable bacterial pathogens to maximize effector function and obtain nutrients, thereby promoting bacterial proliferation.