Diphtheria is an infection caused by toxigenic strains of Corynebacterium diphtheriae. The pathogen releases the toxin that affects heart, kidneys, adrenal gland, as well as spinal and cerebral nerves. Tissue- and organ-specific action of diphtheria toxin is considered to be associated with the blood supply to these organs. We propose the hypothesis that takes into account the physical and chemical properties of the toxin molecule (positively charged R-domain in the B subunit) and cell expression of different types of the HB-EGF receptor and CD9 co-receptor, which are responsible for the toxin penetration into the cell. The proposed hypothesis explains the possible mechanisms of diphtheria complications.