As a leading cause of death globally, cancer is a significant barrier to increasing life expectancy in every country of the world. The general wellness of cancer survivors, including overall quality of life, is a diverse and multidimensional construct that concerns the bio-psycho-social-spiritual wellness of the population. Cancer-related psychological distress, which the National Comprehensive Cancer Network (NCCN) in the United States defines as an “unpleasant emotional experience of a psychological (cognitive, behavioral, and emotional), social, and/or spiritual nature that may interfere with the ability to cope effectively with cancer, its physical symptoms, and its treatment,” is a significant outcome pertaining to cancer survivors’ general wellness. This chapter begins with a high-level overview of cancer-related psychological distress and goes on to review innovative and transdisciplinary methods for both identifying and managing psychological distress among cancer survivors. Approaches for identifying distress include self-report screening tools, artificial intelligence applications, and brain imaging. The management of distress may include emotional and peer support, psychoeducation, and psychotherapeutic interventions, including cognitive behavioral therapy, mindfulness-based, strength-based, and neuroscience-informed perspectives. Throughout, contributions from social work, neuroscience, computer science, artificial intelligence, bimolecular science, implementation science, and others are highlighted. Ultimately, this chapter provides a strong case for a transdisciplinary approach to cancer-related psychological distress.