Calcium plays a fundamental role in the cell as second messenger and is principally regulated by calcium-binding proteins. Although these proteins share in common their ability to bind calcium, they belong to different subfamilies. They present, in general, specific developmental and distribution patterns. Most Purkinje cells express the fast and slow calcium buffer proteins calbindin-D28k and parvalbumin, whereas basket, stellate and Golgi cells the slow buffer parvalbumin only. They are, almost all, calretinin negative. Granule, Lugaro and unipolar brush cells present an opposite immunoreactivity profile, most of them being calretinin positive while lacking calbindin-D28k and parvalbumin. The developmental pattern of appearance of these proteins seems to follow the maturation of neurons. Calbindin-D28k appears early, shortly after cessation of mitosis when neurons become ready to start migration and differentiation while parvalbumin is expressed later in parallel with an increase in neuronal activity. The other proteins are generally detected later. During development, some of these proteins, like calretinin, are transiently expressed in specific cellular subpopulations. The function of these proteins is not fully understood, although strong evidence supports a prominent role in physiological settings with altered calcium concentrations. These proteins regulate and are regulated by intracellular calcium level. For example, they may directly or indirectly enable sensitization or desensitization of calcium channels, and may further block calcium entry into the cells, like the calcium-sensor proteins, that have been shown to be potent and specific modulators of ion channels, which may allow for feedback control of current function and hence signaling. The absence of calcium buffer proteins results in marked abnormalities in cell firing; with alterations in simple and complex spikes or transformation of depressing synapses into facilitating synapses. Calcium-binding protein implication in resistance to degeneration is still a controversial issue. Neurons rich in calcium-binding proteins, especially calbindin-D28k and parvalbumin, seem to be relatively resistant to degeneration in a variety of acute and chronic disorders. However other data support that an absence of calcium-binding proteins may also have a neuroprotective effect. It is not unlikely that neurons may face a dual action mechanism where a decrease in calcium-binding proteins has a first short-term beneficial effect while it becomes detrimental for the cell over the long term.