Background: Commitment to patient engagement in research provides significant opportunities to advance our understanding of patients’ experience whilst fostering sensitivity and progress in research. Yet, people who are frail or seriously ill are rarely given the opportunity to partner across the course of a research study. Little is known about their impact on the conduct of research and the best ways of ‘meaningfully’ involving them as research partners. A series of studies using multiple methods were conducted to explore meaningful engagement of frail and seriously ill patients as partners in research. Study 1: A systematic review with narrative synthesis was conducted to describe the engagement of frail and seriously ill patients as research partners across the research cycle. Thirty eligible studies showed emerging evidence that research partnerships with frail and seriously ill patients can be achieved successfully. Frailty and serious illness present legitimate concerns due to the vulnerability of patient-partners but can be successfully mitigated when researchers ensure timing and methods of engagement are flexible and practical, and emotional needs of patient partners are consistently addressed. Study 2: A qualitative sub-analysis of the prior systematic review was conducted to identify ethical considerations of engaging frail and seriously ill patients as research partners. Findings revealed that researchers and patients should work together to clarify the intent and outcomes of the partnership, actively address relational and intellectual power differentials, recognize and minimize the potential for unintended harm, and strive to maximize the benefits of partnership. Study 3: An analytic autoethnography was conducted to explore how patient engagement is embodied and situated during serious illness. Findings provide a unique contribution to the discourse on representation and contested identity. Current concerns of tokenism are countered through recognition of ways in which patients ‘find’ and ‘make’ meaning through research partnerships. Partnering with seriously ill patients offers enormous potential to advance research through harnessing the power of embodied knowledge production. Conclusion: This dissertation highlights the importance of ensuring that the voices of frail and seriously ill patient-partners’ are heard first-hand. It further demonstrates, the current methodological imperative of patient engagement requires novel approaches to both enacting and evaluating patient engagement.