Fatigue interference with activities, mood, and cognition is one of the most prevalent and distressing concerns of metastatic breast cancer patients. To date, there are no evidence-based interventions for reducing fatigue interference in metastatic breast cancer patients and other advanced cancer populations. In pilot studies, Acceptance and Commitment Therapy (ACT) has shown potential for reducing symptom-related suffering in cancer patients. We recently conducted a pilot study in metastatic breast cancer that tested a novel telephonebased ACT intervention combining mindfulness exercises (e.g., meditations, performing activities with greater awareness) with identification of personal values and engagement in activities consistent with these values. The intervention showed strong evidence of feasibility, acceptability, and promise with respect to reducing fatigue interference with activities, mood, and cognition. The proposed Phase II trial seeks to more definitively examine the efficacy of our telephone-based ACT intervention for women with metastatic breast cancer who are experiencing fatigue interference. In this trial, 250 women will be randomly assigned in equal numbers to either the ACT intervention or an education/support control condition. Women in both conditions will attend six weekly 50-minute telephone sessions. The primary aim of this study is to test the effect of telephone-based ACT on fatigue interference. Secondary outcomes include sleep interference, engagement in daily activities, and quality of life. Outcomes will be assessed at baseline, 2 weeks post-intervention, and 3 and 6 months postintervention. This trial will also examine whether increases in psychological flexibility, defined as full awareness of the present moment while persisting in action aligned with personal values, account for the beneficial effect of ACT on fatigue interference. After demonstrating ACT's efficacy, the intervention can be widely disseminated to metastatic breast cancer patients. This trial will also lay the groundwork for further application and testing of ACT with a wide range of cancer populations and functional outcomes.