Since the 1970s, overall age-adjusted breast cancer mortality rates in the U.S. have been higher among African American (AA) women than among Caucasian American (CA) women. The racial disparity is not fully explainable based on socioeconomic factors. Suspected biologic factors underlying this trend may be interpreted by both epidemiologic and clinical perspectives. Descriptive epidemiologic studies suggest that breast cancer may be a mixture of at least 2 main diseases and/or causal pathways. The first breast cancer is early-onset, with peak incidence near age 50 years and generally more aggressive outcome. The second breast cancer is late-onset, with peak incidence near age 70 years and more indolent course. The early-onset type of breast cancer is overrepresented among AA women compared with CA women. Clinical studies suggest that the course of breast cancer may be characterized by a common pathway through sequential dormant and active states eventually resulting in clustered appearance of clinical metastases. A balance between tumor and host traits influences the pace of the common pathway. Therefore, the recurrence risk profile of a single patient is seemingly determined by a specific mix of hierarchical prognostic factors, resulting from the unique genetic, environmental, or behavioral traits of that individual, which may be affected by race-related factors. We suggest that the components of the AA versus CA disparity not attributable to socioeconomic factors are a particular case of the more general issue of host-tumor interaction and that epidemiologic and clinical views are complementary; each is observing biologic parameters, which are not completely captured by the other. A ‘unifying hypothesis’ incorporating findings from genetics, epidemiology, and clinical studies should be aggressively pursued. Cancer 2007. © 2007 American Cancer Society.