Limiting energy availability via diet or physical activity has health benefits; however, it is not known whether these interventions have similar effects on the development of cancer. Two questions were addressed as follows: (i) Does limiting energy availability by increasing physical activity have the same effect on mammary carcinogenesis as limiting caloric intake? and (ii) Are host systemic factors, implicated as risk biomarkers for breast cancer, similarly affected by these interventions? Female Sprague Dawley rats were injected with 50-mg 1-methyl-1-nitrosourea per kg body weight at 21 days of age and randomized to one of five groups (30 rats per group) as follows: (i) sham running wheel control; (ii) restricted fed to 85% of the sham control; (iii and iv) voluntary running in a motorized activity wheel (37 m/min) to a maximum of 3,500 m/d or 1,750 m/d; and (v) sedentary ad libitum fed control with no access to a running wheel. The three energetics interventions inhibited the carcinogenic response, reducing cancer incidence (P = 0.01), cancer multiplicity (P < 0.001), and cancer burden (P < 0.001) whereas prolonging cancer latency (P = 0.004) although differences among energetics interventions were not significant. Of the plasma biomarkers associated with the development of cancer, the energetics interventions reduced bioavailable insulin-like growth factor-1 (IGF-1), insulin, interleukin-6, serum amyloid protein, TNF-α, and leptin and increased IGF-binding protein 3 (IGFBP-3) and adiponectin. Plasma-fasting glucose, C-reactive protein, estradiol, and progesterone were unaffected. The plasma biomarkers of greatest value in predicting the carcinogenic response were adiponectin > IGF-1/IGFBP-3 > IGFBP-3 > leptin > IGF-1.