Breast cancer is now the leading cause of cancer mortality among women worldwide, with more that 40,000 American women dying from the disease annually. While these statistics are grim, numerous epidemiological studies generally support a protective effect of physical activity for breast cancer. Animal data using voluntary wheel running and invasive cancer models are in line with human epidemiological data suggesting that physical exercise has anti- tumor affects and may be associated with an increase in reactive oxygen species (ROS). Elevated production of mitochondrial ROS (mtROS) is also associated with the promotion of tumor progression, and attenuation of oxidative stress with a mitochondrial targeted antioxidant has been shown to reduce tumor burden and metastasis in an invasive breast cancer mouse model. However, if an anti-tumor effect of running is associated with an increase in ROS, then there is a potential paradox in that any anti-oxidant activity directed to mitochondria might mitigate ROS and prevent anti-tumor affects. There are several mechanistic scenarios involving the tumor microenvironment and tumor associated macrophages where exercise and antioxidants may be compatible, thereby suggesting that physical activity and mitochondrial antioxidants could be complimentary and/or synergistic in suppressing invasive breast cancer by preventing or reversing the pro-tumor cell microenvironment and enhancing an anti-tumor microenvironment. Investigation of oxidative stress in the tumor microenvironment is an area highly relevant to understanding not just the biology of cancer, but also the mechanisms through which regular physical activity mediates changes in normal tissue during tumorigenesis and metastasis. Several antioxidant compounds that target mitochondria, such as the Szeto- Schiller (SS) peptides and mitoQ compounds, are being developed which could easily be tested in preclinical studies for compatibility with exercise training in the treatment and possible prevention of invasive breast cancer.