Chronic health conditions pose a significant burden on the health of Americans, and the number of people with chronic conditions is rapidly rising. In 2000, 125 million Americans had ≥1 chronic conditions. That number rose to an estimated 145 million in 2009, and will further rise to a projected 171 million persons in 2030.1 In addition, today some 26% of adults and 68% of Medicare beneficiaries have ≥2 chronic conditions, and two thirds of total healthcare spending is devoted to their care.1–3 To address this growing challenge, the US Department of Health and Human Services (HHS) created the Multiple Chronic Conditions (MCC) Interagency Workgroup, a department-wide effort to address the needs of people with MCC and the health systems that serve them. The Strategic Framework on Multiple Chronic Conditions,4 released by HHS in 2010 as a result of this effort, is designed to address the challenge of MCC across the spectrum of all population groups through 4 overarching goals: Fostering healthcare and public health system changes to improve the health of individuals with multiple chronic conditions. Maximizing the use of proven self-care management and other services by individuals with multiple chronic conditions. Providing better tools and information to healthcare, public health, and social services workers who deliver care to individuals with multiple chronic conditions. Facilitating research to fill knowledge gaps about, and interventions and systems to benefit, individuals with multiple chronic conditions. The papers in this supplement, resulting from 45 MCC research grant awards made by the Agency for Healthcare Research and Quality (AHRQ) that make up the AHRQ MCC Research Network, offer important findings and commentary addressing these goals. First, although newer, more coordinated models of care now exist, such as the patient-centered medical home and accountable care organizations (goal 1), patients with MCC may be less likely than patients without MCC to benefit from these innovations, and more likely to experience fragmented care. Second, although much is required of many MCC patients in managing their care (goal 2), complex treatment regimens can often prove burdensome for patients to follow. The researchers in the MCC Research Network studied how health systems and healthcare professionals can better partner with patients living with MCC to create patient-centered management plans. The articles in the supplement also propose and describe useful tools for the care of patients with MCC (goal 3), including a new scale to measure patients’ ability to follow treatment regimens they are asked to follow and new treatment guidelines for the joint management of several comorbid conditions. Finally, many of the articles contribute to mapping the landscape for future MCC research (goal 4), through a new conceptual model, description of methodological challenges in MCC research and possible remedies, and intriguing descriptive data that poses new questions for future researchers. HHS remains committed to leading the way on improving the care of patients with MCC. Important opportunities in this area include rapid analyses of secondary data to further develop clinical guidelines for patients with MCC, inclusion of patients with MCC in clinical trials, and development of effective behavioral interventions and useful quality measures for front-line providers caring for patients with MCC. The National Institutes of Health recently issued 4 important new funding opportunity announcements in these areas.5–8 However, HHS cannot meet the needs of MCC patients alone. We welcome the participation of public and private sector stakeholders who wish to take a coleadership role in expanding knowledge about the care of this population and rapidly translating research findings into practice. We hope you enjoy these pages and look forward to working with public and private partners to better guide, empower, and support patients with MCC and the healthcare professionals who serve them. We applaud the 45 AHRQ grantees comprising the AHRQ MCC Research Network for their ground breaking accomplishments to date. ACKNOWLEDGMENTS The authors would like to thank Therese Miller, DrPH, the Project Officer at AHRQ, and the guest editors Mary Tinetti, MD and Jayasree Basu, PhD for their intellectual contributions and for making this supplement possible. They would also like to thank the Medical Care staff, including the Deputy Editors, Amy Rosen, PhD, and Robert Weech-Maldonado, MBA, PhD, the Publisher, Druanne Martin, the Managing Editor, Karen Doyle, and the Abt Associates team, Lisa LeRoy, MBA, PhD, Melanie Wasserman, PhD, Meghan Woo, PhD, and Emma Oppenheim, for their technical contributions and logistical support.