In addition to its role in protein synthesis, which involves a peptidyl transferase activity, the ribosome has also been described to be able to assist protein folding, at least in vitro, as presented in a Research Highlight (Das, et al., Biotechnol. J. 2008). This in vitro-described ribosome-borne protein folding activity (RPFA) is yet poorly characterized in vivo, in part because of the lack of tools to study its biological significance. There is substantial evidence documenting RPFA in vitro, and an assay intended to detect this activity in vivo has been set up in bacteria, but this assay is indirect. In this review, we describe the different tools and tests currently available to study RPFA. We put a special emphasis on the various available inhibitors of this activity and in particular, we discuss the use of 6-aminophenanthridine (6AP) and guanabenz (GA), two antiprion drugs that were very recently shown to specifically inhibit RPFA in vitro without any significant effect on the activity of the ribosome in protein synthesis. Therefore, these drugs should allow determining the potential biological role of RPFA. Importantly, the biological activity of 6AP and GA suggest a possible involvement of RPFA in human proteinopathies.