Mechanisms of synaptic and behavioral plasticity in mammalian systems have largely focused on postsynaptic signal transduction cascades involved in long-term synaptic plasticity. Decades of work in highly tractable, ‘simpler’ systems such as the marine mollusk Aplysia, however, have implicated significant involvement of presynaptic mechanisms. This chapter will focus on presynaptic mechanisms of both short- and long-term mammalian central nervous system synaptic plasticity and the role of presynaptic plasticity in learning and memory. Overviews of presynaptic neurotransmitter release, mechanisms of presynaptically mediated short- and long-term plasticity, and the role of presynaptic plasticity in learning and memory are provided. This is followed by individual examples of presynaptic molecules and their potential link to synaptic plasticity or learning and memory.