Sexual and gender diverse (SGD) individuals have unique lived experiences across the lifespan that contribute to health disparities and influence cancer risk and outcomes. Biopsychosocial factors contribute to trauma and medical mistrust with suboptimal engagement with healthcare and cancer-preventive screenings. These factors contribute to cancer disparities among SGD people. A lack of inclusive and affirming practices within cancer clinical trials also contributes to this problem. Dismantling exclusionary research practices requires strategic action. We advocate for sexual orientation and gender identity (SOGI) data collection as well as thoughtful design and conduct of clinical trials that consider the role of intersectionality and minority stress. Exploring SGD cancer patients’ lived experiences and medical histories in a sensitive and affirming manner will help us learn about factors influencing treatment adherence and prognosis. The current manuscript outlines a paradigm shift in the conduct of clinical trials from early conceptualization through dissemination and implementation in order toinclude, affirm, and empowerSGD people with cancer. We provide an overview of culturally responsive practices that should be implemented at each phase of the research process. These enhancements to conventional trial procedures will promote the long-term goal of improving the safety and efficacy of cancer treatments for SGD patients. We also discuss methods for SGD community engagement, research personnel training, and considerations for working with SGD people in industry-funded clinical trials. Advancing clinical and research competencies along these guidelines are fundamental to promoting the inherent value of SGD patients’ lives and more equitable outcomes across the cancer care continuum.