The granule cells (GrC) are the smallest and most numerous neurons of the brain and constitute the main elements of the granular layer of cerebellum, where they are thought to determine a complex spatio-temporal reconfiguration of incoming signals. GrC functioning is based on some specific properties (D’Angelo, Cerebellar granule cell. In: Handbook of the cerebellum and cerebellar disorders (Springer, ed). Springer, Berlin, pp 765–791, 2013): 1. GrCs have a special structure and connectivity pattern allowing fast combinatorial processing 2. GrC are connected to mossy fibers (MFs) and Golgi cells (GoCs) in glomeruli allowing neurotransmitter spillover and crosstalk 3. GrCs are silent at rest and respond with spike bursts to MF activity by exploiting specific ionic channel properties 4. GrCs are at the core of a complex NMDA- and NO-dependent system that regulates long-term synaptic plasticity in MFs and parallel fibers (PFs). 5. GrCs have a peculiar postnatal development determining their connectivity with MFs and Purkinje cells (PCs) (see Chaps. 13, 15, 17, 18).