The critical role for GATA family proteins in maintaining the normal (non-transformed) cell state is corroborated by the recent findings of mutations or methylation in GATA genes both in primary cancers and tumor lines including breast. Previously, microarray profiling studies determined that the highest expression of both GATA3 and ESR1 (estrogen receptor alpha) is seen in tumors associated with the most favorable survival outcomes, whereas the lowest expression of GATA3 is detected in tumor subtypes showing the worst outcomes. At this time, genes and pathways that are regulated by GATA3 in the mammary gland are not well defined. We have previously established a requirement for FOG (Friend Of GATA) cofactors during mouse development. Here we report that in the murine mammary gland Fog2 gene expression is upregulated upon pregnancy and lactation with prominent expression in the epithelial cells of the gland during post-lactational regression. Mammary-specific deletion of Fog2 identified a role for this gene during gland involution; excision of the Fog2 gene leads to the accelerated involution of the gland despite diminished levels of the remodeling enzymes. Importantly, the levels of several genes linked to the control of cancerous transformation in the breast (Esr1, Prg and Foxa1) are significantly reduced upon Fog2 excision. This implicates FOG2 in the maintenance of epithelial cell differentiation in the mammary gland and in performing a protective role in breast cancer.