Much is known about the structure function relationships of a large number of bacterial protein toxins, the nature of their cell surface receptors, and their enzymatic activities which lead to the inactivation of their respective cytosolic targets. Despite this wealth of knowledge a detailed understanding of the mechanisms which underlie translocation of the catalytic domain across the eukaryotic cell membrane to the cytosol, the penultimate event in the intoxication process, have been slow in developing. In the case of diphtheria toxin, two prominent hypotheses have been advanced to explain how the catalytic domain is translocated from the lumen of endocytic vesicles to the target cell cytosol. We discuss each of these hypotheses and provide an overview of recent observations that tend to favor a mechanism employing a Cytosolic Translocation Factor complex in the entry process. This facilitated mechanism of translocation appears to rely upon protein-protein interactions between conserved domains within the transmembrane domain of diphtheria toxin with host cell factors to effect delivery of the enzymatic moiety. We have recently identified a 10 amino acid motif in the transmembrane domain of diphtheria toxin that is conserved in anthrax Lethal and Edema Factors, as well as in botulinum neurotoxins A, C and D. Stable eukaryotic cell transfectants that express a peptide containing this motif become resistant to the toxin, and sensitivity is completely restored by co-expression of siRNA which inhibits peptide expression. Data obtained from use of the protein fusion toxin DAB(389)IL-2 in cytotoxicity assays using susceptible Hut 102/6TG and resistant transfectant Hut102/6TG-T1 cells, as well as pull down assays have led to the formulation of a working model of facilitated delivery of the diphtheria toxin catalytic domain to the cytosol of target cells which is discussed in detail.