Epigenetics describes heritable changes to gene expression, without alterations to the underlying DNA sequence. X chromosome inactivation (XCI) is a model epigenetic process that results in the silencing of one of the two X chromosomes in female mammals. Smchd1 is an epigenetic modifier involved in transcriptional repression that is critical for the maintenance of XCI. Smchd1 has been implicated in several epigenetic phenomena, but the molecular mechanisms by which Smchd1 is involved in transcriptional repression are unknown. Here we describe two approaches to identify functional interactions between Smchd1 and other epigenetic modifiers, using our bespoke retroviral shRNA library. Mouse embryonic fibroblasts (MEFs) generated from E14.5 embryos carrying our previously generated Smchd1-GFP knock-in allele show an enrichment of Smchd1-GFP on the inactive X chromosome (Xi). We used validated hairpins to target 29 epigenetic modifiers involved in XCI, and screened live cells for delocalisation of Smchd1-GFP from the Xi. Knockdown of HnrnpU resulted in the loss of Smchd1-GFP localisation in a subset of cells. Smchd1 and HnrnpU did not Co-Immunoprecipitate, suggesting that Smchd1 and HnrnpU interact indirectly. HnrnpU anchors ncRNA Xist to the Xi, and loss of Smchd1-GFP localisation upon HnrnpU knockdown raises the possibility that Smchd1 localisation to the Xi is Xist dependent. We also screened for synthetic lethal interactions between Smchd1 and enzymatic epigenetic modifiers, targeting 130 genes with 914 shRNAs, in Smchd1 null and wild-type Eµ-MycTg/+ pre-B lymphoma cells, and MEFs. Preliminary analysis suggests that Smchd1 may be involved in chromatin remodeling and sumoylation pathways. These findings suggest mechanisms for Smchd1 localisation to the Xi, and epigenetic pathways in which Smchd1 may function, and also demonstrate that our shRNA library is a unique resource for the characterisation of novel epigenetic modifiers.