Neuronal calcium sensors (NCS) readily bind calcium and undergo conformational changes enabling them to interact and regulate specific target molecules. These interactions lead to dynamic alterations in protein trafficking that significantly impact upon synaptic function. Emerging evidence suggests that NCS and alterations in Ca(2+) mobilization modulate glutamate receptor trafficking, subsequently determining the expression of different forms of synaptic plasticity. In this review, we aim to discuss the functional relevance of NCS in protein trafficking and their emerging role in synaptic plasticity. Their significance within the concept of "translational neuroscience" will also be highlighted, by assessing their potential as key molecules in neurodegeneration.