A robust cellular homeostasis must be maintained in mammary epithelial cells (MECs) to allow for lactation and prevent cancer development. The cGAS-STING pathway is an important player in innate immunity, but the role of STING (stimulator of interferon genes) in maintaining tissue homeostasis during development remains unclear. Here, Weston Porter and colleagues demonstrate that STING plays a crucial role in the mouse mammary gland development. Using an in vitro model, the authors observe that STING is rapidly activated in the presence of MEC differentiation hormonal cues in a cGAS-independent manner. They find that the loss of SIM2, a tumour suppressor, diminishes STING expression, implicating SIM2 as a potential regulator of STING during lactogenic differentiation. Additionally, the authors find that STING is activated in response to mitochondrial reactive oxygen species production during MEC differentiation, suggesting a role of STING in maintaining an inflammatory balance, which has implications in diseases, including cancer. They then demonstrate that loss of STING activity impairs lactation in a STING loss-of-function mouse model, resulting in pups gaining less weight and having a higher rate of mortality. Interestingly, the authors observe differences in the effect of loss of STING between the thoracic and inguinal mammary glands. Overall, the authors demonstrate that STING has a role in maintaining cellular homeostasis during mammary gland development.