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Finding the best route to navigate the changing landscape of healthcare has become an obsession for many organizations. Their quest to stay competitive, significant, and ultimately relevant is a continuous discovery process. Many hospitals and health systems have considered affiliations and partnerships as important tactical options. Partnerships can range from loose arrangements, such as nonequity collaborations and management agreements, to total affiliation, as in a merger and acquisition. Whichever option an organization decides to pursue, a comprehensive assessment is necessary to find the best partner—the right fit. Addressing the “why,” “when,” “how,” and “with whom” questions is fundamental. Having the depth and breadth of resources to manage the discovery process is equally important.Learning from others who have experienced this journey is helpful, as is the support of industry experts. However, one task that cannot be delegated is discerning whether affiliation is right for an organization. That is the responsibility of an organization’s leadership team, which must consider the dynamic forces in play when evaluating an affiliation partnership. Many of the suggested modalities revolve around how the affiliation partnership can provide a value proposition for the entities involved. Furthermore, inevitable challenges emerge when fiercely independent and successful organizations come together at different levels of need and readiness. Anticipating and providing for the potential exit of any member are matters that the partnership must accept and prepare for, and the ability to execute can make or break the trajectory toward a value proposition. A strong resolve to monitor, measure, calibrate, and recalibrate can give a partnership the agility to pivot toward relevance and sustainability.Stratus Healthcare applied principles of alignment and affiliation in creating the largest collaborative partnership of hospitals in the southeastern United States. Drawing from its affiliation partnership experience with Navicent Health and other member organizations, it has many lessons to share.