Context Managing symptom clusters or multiple concurrent symptoms in patients with advanced cancer remains a clinical challenge. The optimal processes constituting effective management of symptom clusters remain uncertain. Objectives To describe the attitudes and strategies of clinicians in managing multiple co-occurring symptoms in patients with advanced cancer. Methods Semistructured interviews were conducted with 48 clinicians (palliative care physicians [n = 10], oncologists [n = 6], general practitioners [n = 6], nurses [n = 12], and allied health providers [n = 14]), purposively recruited from two acute hospitals, two palliative care centers, and four community general practices in Sydney, Australia. Transcripts were analyzed using thematic analysis and adapted grounded theory. Results Six themes were identified: uncertainty in decision making (inadequacy of scientific evidence, relying on experiential knowledge, and pressure to optimize care); attunement to patient and family (sensitivity to multiple cues, prioritizing individual preferences, addressing psychosocial and physical interactions, and opening Pandora's box); deciphering cause to guide intervention (disaggregating symptoms and interactions, flexibility in assessment, and curtailing investigative intrusiveness); balancing complexities in medical management (trading off side effects, minimizing mismatched goals, and urgency in resolving severe symptoms); fostering hope and empowerment (allaying fear of the unknown, encouraging meaning making, championing patient empowerment, and truth telling); and depending on multidisciplinary expertise (maximizing knowledge exchange, sharing management responsibility, contending with hierarchical tensions, and isolation and discontinuity of care). Conclusion Management of symptom clusters, as both an art and a science, is currently fraught with uncertainty in decision making. Strengthening multidisciplinary collaboration, continuity of care, more pragmatic planning of clinical trials to address more than one symptom, and training in symptom cluster management are required.