Südhof is credited with discovering much of the machinery mediating neurotransmitter release and presynaptic plasticity, beginning with the discovery of symaptotagmins and their role in neurostrasmitter release from the presynaptic neuron.

In 2013 Südhof shared the Nobel Prize in Physiology or Medicine with James E. Rothman and Randy W. Schekman "for their discoveries of machinery regulating vesicle traffic, a major transport system in our cells."