Background: With nearly 200,000 new invasive breast cancer diagnoses yearly and a nearly 90% 5 year survival rate, the number of survivors is expected to grow steadily. The primary challenges faced by these women can be divided into two broad categories: 1) persistent adverse effects of treatment and 2) recurrence. Research supports a key role for exercise and weight loss in controlling these survivorship challenges. The overarching goal of the WISER Survivor Trial is to examine the efficacy of exercise and/or weight loss to improve breast cancer-related lymphedema (BRCL) AND to reduce risk for recurrence, as evaluated by levels of biomarkers hypothesized to be along the causal pathway between energy balance and recurrence. Methods: Eligible participants were female breast cancer survivors who had completed treatment at least six months prior to randomization, BMI > 25 but < 50, stable BCRL, age < 80, ability to walk 6 min. unaided, no plans for curative or reconstructive surgery during the study, no self-report of weight lifting or > 90 weekly minutes of aerobic activity in prior 12 months. Recruitment of 351 women was completed in 38 months. The majority of participants (74%) were recruited through letters sent by tumor registries. Exercise prescription: 2x weekly resistance training and walking 180 min/wk. Participants meet with trainers weekly for six weeks, followed by monthly sessions to one year. Adjustable dumbbells shipped directly to participant homes facilitate adherence to the home based exercise program. Weight loss intervention: 24 weekly group behavioral counseling sessions with a registered dietitian, including 20 weeks of meal replacement programming. Weight loss groups continue to meet monthly through the end of the one year intervention. Outcomes include changes in arm swelling as measured by perometry and changes in biomarkers for recurrence, including markers of growth factors, inflammation, and oxidative stress. All participants have completed 6 month assessments. Adherence to the exercise protocol has been consistently over 80%. A total of 228 women have completed the trial, with another 50 still undergoing follow-up. Data collection is expected to be complete by June 2016, with results to be reported in 2017. Clinical trial information: NCT01515124