Abstract: Cadmium (Cd) is a toxic heavy metal ubiquitously distributed in the environment (water, air, food, smoke) with extreme ability to accumulate in the human body due to its delayed clearance (half-life time 15–30 years). Consequently, prolonged exposure to low doses of Cd causes multi-organ toxicity. Remarkably, the central and peripheral nervous systems are considered as one of the most vulnerable targets. Excessive Cd exposure can profoundly aggravate common neurodegenerative diseases and peripheral polyneuropathies as well as lead to mental deficits in children (Branca et al., 2020). Conceivably, that Cd-induced defects in communication between neurons could be triggering events in Cd neurotoxicity. Numerous studies have discovered the disturbances at the synaptic levels in response to both acute and chronic Cd administration. Furthermore, release of Cd, captured by neuronal tissue, into extracellular space is increased by stimulation of synaptic vesicle (SV) exocytosis (Minami et al., 2001), pointing to Cd accumulation within the SVs in presynaptic terminals. Being a divalent cation, Cd can enter cells through various ways (such as active transporters, carriers, channels, and endocytosis), which serve to transport physiologically essential cations (Ca, Mg, Cu, Mn, Zn). An important route for Cd penetration into neuronal cells relies on zinc transporters (ZnTs). Among them, ZnT3 is highly abundant in the membranes of the SVs and responsible for maintaining the vesicular Zn pool in brain (McAllister and Dyck, 2017). Presumably, presynaptic terminals containing from hundreds to thousands of SVs could be reservoirs for Cd accumulating in the SVs due to ZnT3 activity. Furthermore, SV membranes are enriched with anionic negatively-charged lipids that can electrostatically attract bivalent cations, including Cd. Likewise, voltage-gated Ca2+ channels (VGCCs), which are reversibly blocked by Cd, reside densely at the presynaptic site can concentrate Cd, facilitating its uptake. Moreover, Cd may slowly pass into the cytosol through some of the VGCCs. Inside the nerve terminals Cd could affect a plethora of processes, consequently disturbing various presynaptic functions, notably neurotransmitter release. The resulting synaptic defects can produce “devastating signals” which are propagated to the neuronal bodies. Such retrograde pattern of pathology spreading is observed in some neurodegenerative disorders. Recently, we have found that at very low concentrations Cd can desynchronize neurotransmitter release from motor nerve terminals (Tsentsevitsky et al., 2020). A focus on the mechanism behind this phenomenon (Figure 1) can delineate the early events in Cd neurotoxicity and reveal a bridge between Cd action and neurodegeneration.