Understanding how DON induces rRNA degradation will provide insight into the mechanisms by which trichothecenes and other ribotoxins incapacitate or kill immunocompetent cells. The results presented here establish for the first time that (1) DON-induced cleavage at a limited number of sites in both 18S rRNA and 28S rRNA, (2) these cleavages result from PKR-driven p38 activation, (3) these events closely parallel induction of apoptosis by this mycotoxin, and (4) DON's effects are shared with other ribotoxic agents.