BACKGROUND AND OBJECTIVES: Multimorbidity, the coexistence of two or more chronic conditions, affects about 40% of all adults and over half of adults over 60 years. The complexity of multimorbidity (MM) often renders traditional trial designs inadequate, unable to account for the context of interventions, including the interplay of multiple health conditions in daily life. This gap reduces the generalizability and applicability of their results. METHODS: This commentary aims to review the current state of trials targeting or involving patients with MM. Highlighting current limitations and drawing on insights from an international dedicated workshop in Bielefeld, Germany, we identify an ongoing and pressing need for innovative, patient-centered approaches to their design and conduct. RESULTS: We propose a shift toward more holistic and integrative experimental approaches, including developing interventions tailored to the characteristics and needs of patients with MM, establishing relevant outcomes, and enhancing data collection and process evaluation. We specifically advocate for adaptive trial designs, prespecified subgroup analyses, and the incorporation of patient-reported outcomes and experience measures such as burden of care to ensure that research is both comprehensive and reflective of the needs of patients living with MM, their caregivers, and of the clinicians participating in their care. Ethical considerations are discussed in our commentary as well, emphasizing the importance of patient safety, data protection, and informed consent. Finally, we call for the development of specific reporting guidance, such as a SPIRIT extension tailored to MM trials, to help researchers adapt standard protocols to the complex and heterogeneous reality of this population. CONCLUSION: This commentary aims to bridge the gap between research and practice, fostering the development of effective interventions that improve patient outcomes and enhance the quality of care for patients living with MM.