Genetic compensation usually occurs when polymorphic modifier genes provide robust compensation for the loss of a gene of interest. The epidermal growth factor receptor (EGFR) is a critical gene for early development. Its disruption can cause abnormal embryonic and placental development, and it is implicated in tumorigenesis. Mouse embryos lacking Egfr have reduced proliferation in trophoblast stem cell lineages that form the spongiotrophoblast layer of the placenta. Depending on severity, this can impact the labyrinth layer, the size of the placenta, and the timing and frequency of embryonic lethality. These placental phenotypes are strongly dependent on genetic background, indicating the presence of Egfr modifier genes. We crossed the ALR/LtJ mouse strain, a robust survivor with Egfr loss, to the 129S1/SvImJ, which have a mid-gestation lethality phenotype due to placental dysfunction, to show that hybrid ALR.129 Egfr-null embryos survive into late gestation. Using a phenotypic congenic approach, we generated evidence suggesting the presence of three dominant loci. We are using a reverse genetics approach to identify the Egfr modifiers by investigating dysfunction of known trophoblast stem (TS) cell lineage pathways. We utilized 129S1 and ALR mice that are homozygous for a conditional Egfr allele (Egfrtm1.1Dwt) to generate TS cells. The introduction of Cre recombinase into TS cells by electroporation induces recombination at the loxP sites deleting Egfr, which provides genetically matched TS cell lines with and without EGFR. We are using these cell lines to elucidate candidate Egfr modifier genes capable of compensating for loss of EGFR. The findings will aid in the identification of modifier genes of Egfr that may influence the severity of conditions related to malformed placentas, such as intrauterine growth restriction, and may impact the effectiveness of EGFR-targeted cancer chemotherapies.