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The most impactful research in critical care comes from trials groups led by clinician-investigators who study questions arising through the day-to-day care of critically ill patients. The success of this model reflects both “necessity”—the paucity of new therapies introduced through industry-led research—and “clinical reality”—nuanced modulation of standard practice can have substantial impact on clinically important outcomes. Success in a few countries has fueled efforts to build similar models around the world and to collaborate on an unprecedented scale in large international trials. International collaboration brings opportunity—the more rapid completion of clinical trials, enhanced generalizability of the results of these trials, and a focus on questions that have evoked international curiosity. It has changed practice, improved outcomes, and enabled an international response to pandemic threats. It also brings challenges. Investigators may feel threatened by the loss of autonomy inherent in collaboration, and appropriate models of academic credit are yet to be developed. Differences in culture, practice, ethical frameworks, research experience, and resource availability create additional imbalances. Patient and family engagement in research is variable and typically inadequate. Funders are poorly equipped to evaluate and fund international collaborative efforts. Yet despite or perhaps because of these challenges, the discipline of critical care is leading the world in crafting new models of clinical research collaboration that hold the promise of not only improving the care of the most vulnerable patients in the healthcare system but also transforming the way that we conduct clinical research.