The accumulation of high local concentrations of excitatory amino acids, particularly glutamate, is involved in neuronal cell death in neurodegenerative diseases such as stroke, trauma, Huntingtons disease, and amyotrophic lateral sclerosis. Accumulation of glutamate leads to excessive Ca2+ influx into the neuron. The molecules involved in neuronal degeneration following intracellular Ca2+ overload have been identified. Calcineurin and calpain, a Ca2+/calmodulindependent protein phosphatase and Ca2+-dependent cysteine protease, respectively, are two of the most important Ca2+- dependent effectors during neuronal degeneration. These two molecules have been thought to mediate neuronal degeneration through independent cascades. However, recent studies have shown that a cross-talk pathway exists between calcineurin and calpain in neurons and the pathway plays a critical role in excitotoxic neuronal degeneration. This review covers recent findings regarding the cross-talk pathway involved in neuronal degeneration and novel neuroprotective reagents that block the signal pathway.