Children with medical complexity (CMC) have severe, chronic conditions that require intensive care and are not easily met by existing healthcare models. CMC may have congenital or acquired multisystem diseases, severe neurological conditions, or cancer survivors with ongoing disabilities. These children face significant health and family challenges, but there are few well-characterized clinical initiatives or research efforts to improve their care. The authors present a definitional framework for CMC, including substantial family-identified service needs, chronic conditions, functional limitations, and high healthcare use. They also explore existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. A research agenda is proposed to use a uniform definition to accurately describe the population and evaluate outcomes from the perspectives of the child, family, and broader healthcare system. CMC are likely increasing in prevalence due to improved survival rates and treatments for infants born prematurely, children with congenital anomalies, and those with chronic conditions. CMC require intensive hospital and community-based services, technology, polypharmacy, and home care. The need for coordinated care is underscored by the emergence of novel complex care programs across North America. However, meaningful evaluation of these programs is limited by a lack of agreement on a definition of CMC and the absence of a clinical and research agenda. The authors propose a definitional framework for CMC and a clinical and research agenda to improve the quality of healthcare for CMC and their families. The framework includes four domains: needs, chronic conditions, functional limitations, and healthcare use. The authors also discuss the importance of a research agenda that uses a uniform definition to accurately describe the population and evaluate outcomes from the perspectives of the child, family, and broader healthcare system. The research agenda includes addressing condition-specific and condition-independent outcomes, measuring mental health, and ensuring seamless healthcare transitions for adolescents and young adults. The authors conclude that CMC pose important challenges to families, providers, and the healthcare system, and that the development of novel complex care programs suggests that traditional systems of care may not be meeting the substantial needs of such patients and their families. The creation of sustainable evidence-based models of care is essential for enhancing the quality of life and outcomes for these children.Children with medical complexity (CMC) have severe, chronic conditions that require intensive care and are not easily met by existing healthcare models. CMC may have congenital or acquired multisystem diseases, severe neurological conditions, or cancer survivors with ongoing disabilities. These children face significant health and family challenges, but there are few well-characterized clinical initiatives or research efforts to improve their care. The authors present a definitional framework for CMC, including substantial family-identified service needs, chronic conditions, functional limitations, and high healthcare use. They also explore existing care models and apply the principles of the chronic care model to address the clinical needs of CMC. A research agenda is proposed to use a uniform definition to accurately describe the population and evaluate outcomes from the perspectives of the child, family, and broader healthcare system. CMC are likely increasing in prevalence due to improved survival rates and treatments for infants born prematurely, children with congenital anomalies, and those with chronic conditions. CMC require intensive hospital and community-based services, technology, polypharmacy, and home care. The need for coordinated care is underscored by the emergence of novel complex care programs across North America. However, meaningful evaluation of these programs is limited by a lack of agreement on a definition of CMC and the absence of a clinical and research agenda. The authors propose a definitional framework for CMC and a clinical and research agenda to improve the quality of healthcare for CMC and their families. The framework includes four domains: needs, chronic conditions, functional limitations, and healthcare use. The authors also discuss the importance of a research agenda that uses a uniform definition to accurately describe the population and evaluate outcomes from the perspectives of the child, family, and broader healthcare system. The research agenda includes addressing condition-specific and condition-independent outcomes, measuring mental health, and ensuring seamless healthcare transitions for adolescents and young adults. The authors conclude that CMC pose important challenges to families, providers, and the healthcare system, and that the development of novel complex care programs suggests that traditional systems of care may not be meeting the substantial needs of such patients and their families. The creation of sustainable evidence-based models of care is essential for enhancing the quality of life and outcomes for these children.