To explore breast cancer etiology, literature was searched using Medline. We explored the 1) plausibility of smoking in breast carcinogenesis; 2) physiological properties, susceptibility windows, and exposure timing of breast cells; 3) role of exogenous hormones in breast carcinogenesis; 4) biological mechanism of synergistic interactions between smoking and exogenous hormones in breast carcinogenesis; and 5) evidence from epidemiologic studies and the fitted secular trend between smoking rate, exogenous hormone use, and breast cancer incidence in past decades. We deduced that exogenous hormone use per se is not a significant cause and its association with breast cancer is distorted by chronic exposure to environmental carcinogens, especially smoking. We hypothesize that smoking is one of the causes of breast cancer and that this causality is strengthened by synergistic interaction between smoking and exogenous hormone use. Physicians should be cautious of prescribing exogenous hormones for those with chronic exposure to environmental carcinogens to prevent breast cancer.