Neurons are an unusual type of cell in that they send processes (axons and dendrites) over great distances. This elaborate morphology, together with their excitability, places neurons at risk for multiple insults. Recent studies have demonstrated that apoptotic and excitotoxic mechanisms not only contribute to neuronal death, but also to synaptic dysfunction and a breakdown in neural circuitry (see Mattson and Duan [1999] J. Neurosci. Res. 58:152–166, this issue). Proteases of the caspase and calpain families have been implicated in neurodegenerative processes, as their activation can be triggered by calcium influx and oxidative stress. Caspases and calpains are cysteine proteases that require proteolytic cleavage for activation. The substrates cleaved by caspases include cytoskeletal and associated proteins, kinases, members of the Bcl‐2 family of apoptosis‐related proteins, presenilins and amyloid precursor protein, and DNA‐modulating enzymes. Calpain substrates include cytoskeletal and associated proteins, kinases and phosphatases, membrane receptors and transporters, and steroid receptors. Many of the substrates of caspases and calpains are localized in pre‐ and/or postsynaptic compartments of neurons. Emerging data suggest that, in addition to their roles in neurodegenerative processes, caspases and calpains play important roles in modulating synaptic plasticity. The present article provides a review of the properties of the different caspases and calpains, their roles in cell death pathways, and the substrates upon which they act. Emerging data are considered that suggest key roles for these proteases in the regulation of synaptic plasticity. J. Neurosci. Res. 58:167–190, 1999. © 1999 Wiley‐Liss, Inc.