Mammals are defined by a unique tissue, the mammary glands, which secrete milk that feed their offspring. Even though a milk supply is vital to species’ survival, the molecular mechanisms that regulate lactation remain obscure. Recent research shows that acquiring nutrients from mother’s milk confers a lifetime of benefits, yet many women around the world are unable to produce sufficient milk to supply the needs of their infant. Establishing therapeutically targetable molecules that drive lactation promises to help women experiencing lactation insufficiency syndrome and expand the health of the population. In my thesis work, I show that the protein Van Gogh-like 2 (VANGL2) plays a novel role in the nucleus where it inhibits differentiation of mammary epithelial cells into milk producing alveolar cells. My data show that VANGL2, working in conjunction with the polycomb repressor protein BMI1, represses the transcription of pro-differentiation genes. Decreasing the nuclear localization of VANGL2 results in precocious differentiation and more milk. This research presents a novel role for VANGL2 in regulating gene transcription at a crucial point in tissue differentiation, making it an appealing clinical target for lactation insufficiency.