Diphtheria toxin (DT)**Abbreviations used in this paper: DT, diphtheria toxin; DT-C, DT catalytic fragment; DT-T, DT transmembrane; EF-2, elongation factor 2. is the paradigm of the powerful A-B toxins. These bacterial poisons bind to cells, are endocytosed, and inject their catalytic domain into the cytosol causing the irreversible modification of a key component of the the host cellular machinery. The mechanism by which the hydrophilic enzymatic fragment of DT crosses the endosomal membrane and is released into the cytosol remains controversial. In this issue, Ratts et al. (2003) demonstrate that delivery of the DT catalytic domain from the lumen of purified early endosomes to the external medium requires the addition of a cytosolic translocation factor complex composed in part of Hsp90 and thioredoxin reductase.