Convincing evidence now supports a probable preventive role for physical activity in postmenopausal breast cancer. The mechanisms by which long-term physical activity affect risk, however, remain unclear. The aims of this review were to propose a biological model whereby long-term physical activity lowers postmenopausal breast cancer risk and to highlight gaps in the epidemiologic literature. To address the second aim, we summarized epidemiologic literature on 10 proposed biomarkers, namely, body mass index (BMI), estrogens, androgens, sex hormone binding globulin, leptin, adiponectin, markers of insulin resistance, tumor necrosis factor-alpha, interleukin-6, and C-reactive protein, in relation to postmenopausal breast cancer risk and physical activity, respectively. Associations were deemed "convincing," "probable," "possible," or "hypothesized" using set criteria. Our proposed biological model illustrated the co-occurrence of overweight/obesity, insulin resistance, and chronic inflammation influencing cancer risk through interrelated mechanisms. The most convincing epidemiologic evidence supported associations between postmenopausal breast cancer risk and BMI, estrogens, and androgens, respectively. In relation to physical activity, associations were most convincing for BMI, estrone, insulin resistance, and C-reactive protein. Only BMI and estrone were convincingly (or probably) associated with both postmenopausal breast cancer risk and physical activity. There is a need for prospective cohort studies relating the proposed biomarkers to cancer risk and for long-term exercise randomized controlled trials comparing biomarker changes over time, specifically in postmenopausal women. Future etiologic studies should consider interactions among biomarkers, whereas exercise trials should explore exercise effects independently of weight loss, different exercise prescriptions, and effects on central adiposity.