Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by a lack of gene expression at the imprinted PWS cluster. PWS patients all preserve a normal yet epigenetically silenced copy of PWS genes. We are investigating SMCHD1, a known epigenetic repressor with a role in silencing at the PWS locus, as a potential target for gene activation therapy in PWS patients. Using mouse models we have confirmed in vivo activation of imprinted PWS genes following Smchd1 deletion and a resulting improvement in some disease phenotypes. We also observe PWS gene activation following SMCHD1 depletion in human patient-derived cells. Taken together these data support the feasibility of targeting SMCHD1 for epigenetic therapy in PWS.