Background: The use of disease-specific patient-reported outcomes (PROs) is critical for facilitating individualized symptom monitoring and improving cancer patient outcomes. The MD Anderson Symptom Inventory (MDASI) is a PRO measure of symptom burden. The purpose of this study was to describe the patient experience and define the content domain for the MDASI module specific to breast cancer (MDASI-Br). Methods: 36 patients with breast cancer across the disease and treatment continuum described their experience in single qualitative interviews. Content analysis was used to define the symptom burden content domain. An expert panel scored the relevance on a 0–4 scale (4 = relevant) of the symptoms identified from the qualitative interviews. Symptoms were selected for inclusion in the MDASI-Br if they met at least 1 of the following criteria: (1) mean relevance rating of ≥3 by the expert panel, (2) described by ≥20% of patients in qualitative interviews, or (3) core MDASI items. Results: Participants had a mean age of 57.9 years, 86.1% had stage I–III, and 52.8% were on active treatment. 36 symptoms were identified, with 14 reported by ≥20% of participants. Symptoms varied among participants based on disease stage and treatment modality. Fatigue and distress were described by most women regardless of treatment, whereas arm swelling was reported only by women who had undergone surgery, and skin changes were reported primarily by women who received radiation therapy. Patients volunteered ways in which symptoms affected daily functioning. 21 symptoms were included in the MDASI-Br for psychometric testing, including 6 breast cancer-specific symptoms: breast changes, hot flashes, constipation, arm swelling, fingernail or toenail changes, and skin changes. Two additional symptoms, vaginal dryness and decrease in sexual interest or activity, were included because they are common to endocrine therapy. Conclusions: Patients with breast cancer experience numerous but distinct symptoms related to disease and treatment that may result in interference with daily activities, relationships, life plans, treatment adherence, and mood. Various treatments result in unique symptom burden. The content domain for a PRO symptom-burden measure of breast cancer encompasses the diversity, severity, and activity interference of common symptoms of breast cancer and its treatment.