The majority of the world population smokes or has smoked, and a further proportion is or has been exposed to environmental tobacco smoke. Although recent evidence consistently supports an association between smoking and an increased risk of breast cancer development, progression to metastasis and death, the underlying mechanisms are poorly understood. Here we will assess the effects of exposure to cigarette smoke using mouse models of the most frequent gain-of-function mutation in breast cancer (i.e., mutant phosphatidylinositol 3-kinase (PI3K)). We will directly assess how smoking contributes to breast cancer metastasis in a cell-autonomous (i.e., within cancer cells) or non-cell-autonomous (i.e., immune cells within metastatic sites) manner, and identify and validate the oncogenic molecular and cellular mechanisms involved. We will use a battery of cell biological assays, as well as multiphoton intravital imaging to dissect the mechanisms underlying cigarette smoke-evoked metastasis.