The transcription factor Stat3 is essential for timely initiation of post-lactational regression and orchestrates the processes of cell death and tissue remodelling that occur during the first 6 days of involution in the mouse. Paradoxically, STAT3 is also frequently found to be constitutively active in breast cancer and tumors can become addicted to STAT3. This raises two interesting questions: 1) do the high levels of active Stat3 present in the mammary epithelium during involution promote tumor spread and 2) how do tumor cells escape the pro-apoptotic effects of Stat3? In order to address these questions, it is essential to understand the role of Stat3 in involution and the mechanisms by which Stat3 regulates both cell death and tissue remodelling. A number of studies have been undertaken using genetically modified mice and microarray analyses and two significant findings arose from these investigations. Firstly, post-lactational regression is associated with an acute phase and inflammatory response in addition to cell death and secondly, Stat3 alone is insufficient to induce involution in the absence of the NF-κB regulatory kinase IKKβ. Both Stat3 and NF-κB have been shown to regulate the expression of genes involved in inflammatory signalling and the acute phase response. These findings suggest a role for the innate immune response in mammary epithelial cell fate during involution and highlight potential roles for this response in tissue remodelling-associated breast cancer metastasis.