Botulinum neurotoxins (BoNTs) are the most potent toxins known to humankind. They cause a fetal disease termed botulism, by specifically cleaving SNARE proteins to block neurotransmitter release at nerve terminals. This thesis is dedicated to elucidate how BoNTs translocate from endosomes into the cytosol of neurons, the least understood process during BoNT intoxication. Translocation of BoNT/B and E, two serotypes of BoNTs causing human botulism, were studied. We found that binding to the ganglioside GT1b, a coreceptor for BoNTs, enables BoNT/B to sense low pH, undergo a significant change in secondary structure, and transform into a hydrophobic oligomeric membrane protein. Imaging of the toxin on lipid bilayers utilizing atomic force microscopy revealed donut-shaped channel-like structures that resemble other protein translocation assemblies. Toosendanin, a drug possessing therapeutic effects against botulism, inhibited GT1b-dependent BoNT/B oligomerization and in parallel truncated BoNT/B single-channel conductance, indicating that oligomerization plays a role in the translocation reaction. Thus, BoNT/B functions as a coincidence detector for receptor and low pH to ensure spatial and temporal accuracy for toxin conversion into a translocation channel. We discovered that similar to BoNT/B, BoNT/E is also a coincidence detector for translocation, that binding to GT1b enabled BoNT/E to transform into a hydrophobic protein at the same low pH range as BoNT/B. However, BoNT/E exhibited some distinct properties from BoNT/B. BoNT/E translocated much faster than BoNT/B in neurons. Binding of GT1b enabled BoNT/E to assemble into oligomers even at neutral pH, potentially contributing to its fast translocation. In the absence of GT1b, low pH altered the structure of BoNT/E to some degree that the toxin lost its ability to intoxicate neurons. In summary, our studies indicate that BoNTs may function as coincidence detectors for low pH and GT1b for translocation, that in addition to the well-established role of low pH, receptor molecules may also play a role in shaping the behaviors of these deadly toxins.