Bacteria cope with ribosome stalling thanks to trans-translation, a major quality control system of protein synthesis that is mediated by tmRNA, an hybrid RNA with properties of both a tRNA and an mRNA, and the small protein SmpB. Because trans-translation is absent in eukaryotes but necessary for bacterial fitness or survival, it is a promising target for the development of novel antibiotics. Here I will present four cryo-EM structures of the ribosome during trans-translation. These include the first high-resolution structure of the whole pre-accommodated state, as well as structures of the accommodated state, the translocated state, and a new translocation intermediate. Together, they shed light on the movements of the tmRNA-SmpB complex in the ribosome, from its delivery by the elongation factor EF-Tu to its passage through the ribosomal A and P sites after the opening of the ribosomal bridges. I will also present a medicinal chemistry program that we perform to discover new and specific compounds targeting trans-translation in resistant bacteria.