Obesity is associated with increased risk of breast cancer in postmenopausal women and is linked with poor prognosis in pre- and postmenopausal breast cancer patients. The mechanisms underlying the obesity-breast cancer connection are becoming increasingly clear and provide multiple opportunities for primary to tertiary prevention. Several obesity-related host factors can influence breast tumor initiation, progression and/or response to therapy, and these have been implicated as key contributors to the complex effects of obesity on cancer incidence and outcomes. These host factors include components of the secretome, including insulin, insulin-like growth factor-1, leptin, adiponectin, steroid hormones, cytokines, vascular regulators, and inflammation-related molecules, as well as the cellular and structural components of the tumor microenvironment. These secreted and structural host factors are extrinsic to, and interact with, the intrinsic molecular characteristics of breast cancer cells (including breast cancer stem cells), and each will be considered in the context of energy balance and as potential targets for cancer prevention.