Mutations in the SHANK3 gene have been implicated in a subset of patients with Autism spectrum disorder (ASD) in a gene-dosage dependent manner. Shank3 is a putative scaffold molecule found at the post-synaptic density (PSD), binds multiple partners and has been termed the master scaffolding molecule of the PSD. One of the key interactors of Shank3 is the Homer class of signaling and scaffold molecules. Shank3 and Homer act in concert to regulate spine maturation. Here we describe a novel Homer-dependent mechanism to stabilize Shank3 at the PSD. Both genetic and pharmacological tools can modulate this pathway thus having implications for ASD therapy. Finally, we are making a novel mouse model of SHANK3 that mimics a reported deletion of the Homer-binding domain of Shank3 in patients with ASD. This mouse model will be a useful tool to study the in vivo function of Shank3. Based on our data, we make predictions on the stability of Shank3 in this mouse model and propose a repertoire of biochemical and behavioral tests to link our molecular model with ASD-like behavior.