Shank proteins are multidomain scaffold proteins located at the post synaptic density (PSD) of glutamatergic synapses where they interact with many signaling and scaffolding proteins. Through this interaction, Shank proteins regulate synapse development, spine structure and synaptic plasticity. Deletions, duplications, and coding mutations in all the three SHANK genes are present in several patients with syndromic autism spectrum disorder (ADS) and intellectual disability (ID) underlying the importance of Shank proteins in modulating intracellular signaling pathways that are essential for neuronal functions. However, several evidences suggest that mutation of different SHANK genes, in both human and mice, cause different clinical features suggesting that different Shank family members proteins might have distinct functions in modulating synaptic maturation and function. Understand their specific roles is essential to better define glutamatergic synaptic function and to define molecular pathways that can provide new therapeutic targets to treat patients with SHANK mutations. I will discuss the results obtained in our lab characterizing several in vitro and in vivo animal model that are essential to better define how disruption of SHANK scaffolding proteins affects the formation and function of synapses and neural circuits.