There are distinct subgroups of patients who have historically been underrepresented in most prospective clinical trials in breast cancer, including the youngest and oldest patients, male patients, and those struggling with obesity. Herein, we review current and future directions in research for each of these special populations with breast cancer, highlighting significant knowledge gaps and priorities in tumor biology and heterogeneity, therapeutic decision making promotion of adherence, supportive care, and psychosocial and functional well-being. In younger women, future study should focus on the biological underpinnings of aggressive disease and optimizing adherence and treatment decision making while addressing their unique survivorship needs. The latter includes generating a scientific basis for interruption of therapy for pregnancy. Among older patients, interventions should focus on increasing clinical trial accrual, predicting and mitigating toxicity so that functional status can be optimized, tailoring needs for dose modification, and anticipating life expectancy in the context of competing causes of death. For men with breast cancer, we need worldwide collaboration to answer even basic questions on optimal treatment, supportive care, and survivorship strategies. Finally, for those struggling with obesity, we need to better understand the biological associations with cancer incidence, prognosis and outcome, and how we can best intervene to assure weight loss at the "right time." It is only through highly collaborative, far-reaching, prospective, multidisciplinary, patient-centered, and patient-engaged efforts that we can optimize the physical and psychologic outcomes for all patients with breast cancer.