Simple SummaryObesity is a poor prognostic factor for patients with breast cancer, resulting in increased risk of recurrence and death due to breast cancer. Obesity can affect both the efficacy and toxicity of systemic cancer therapies, including chemotherapy, endocrine therapy, immunotherapy, and targeted therapies. In this review, we summarize the impact of obesity on the clinical outcomes of systemic therapies in patients with breast cancer, describe the molecular mechanisms through which obesity can affect systemic therapies, and highlight additional considerations for treating patients with obesity and breast cancer. Further research that focuses on the clinical outcomes in patients with obesity is needed to guide treatment decision-making.AbstractObesity is defined as a body mass index (BMI) of 30 kg/m2or more and is associated with worse outcomes in patients with breast cancer, resulting in an increased incidence of breast cancer, recurrence, and death. The incidence of obesity is increasing, with almost half of all individuals in the United States classified as obese. Patients with obesity present with unique pharmacokinetics and physiology and are at increased risk of developing diabetes mellitus and cardiovascular disease, which leads to specific challenges when treating these patients. The aim of this review is to summarize the impact of obesity on the efficacy and toxicity of systemic therapies used for breast cancer patients, describe the molecular mechanisms through which obesity can affect systemic therapies, outline the existing American Society of Clinical Oncology (ASCO) guidelines for treating patients with cancer and obesity, and highlight additional clinical considerations for treating patients with obesity and breast cancer. We conclude that further research on the biological mechanisms underlying the obesity–breast cancer link may offer new treatment strategies, and clinicals trials that focus on the treatment and outcomes of patients with obesity and all stages of breast cancer are needed to inform future treatment guidelines.