Members of the ATP-binding cassette (ABC)-F protein subfamily collectively mediate resistance to a broader range of clinically important antibiotic classes than any other group of resistance proteins and are widespread in pathogenic bacteria. Following over 25 years' of controversy regarding the mechanism by which these proteins work, it has recently been established that they provide antibiotic resistance through the previously recognized but underappreciated phenomenon of target protection; they bind to the ribosome to effect the release of ribosome-targeted antibiotics, thereby rescuing the translation apparatus from antibiotic-mediated inhibition. Here we review the ABC-F resistance proteins with an emphasis on their mechanism of action, first exploring the history of the debate about how these proteins work and outlining our current state of knowledge and then considering key questions to be addressed in understanding the molecular detail of their function.