This article synthesizes knowledge on the role of relationships and key macro- and micro-contexts -- poverty, racism, families, communities, schools, and peers - in supporting and/or undermining the healthy development of children and youth, using a relational developmental systems framework. Relationships with parents, siblings, peers, caregivers, and teachers are explored in the context of early care and childhood settings, schools, classrooms, and school-based interventions. Additional contextual factors include; chronic stress, institutionalized racism, stereotype threat, and racial identity. A companion article focuses on how the human brain develops, and the major constructs that define human development, the constructive nature of development, and the opportunities for resilience. Human development occurs through reciprocal coactions between the individual and their contexts and culture, with relationships as the key drivers. Relationships and contexts, along with how children appraise and interpret them, can be risks and assets for healthy learning and development, and their influence can be seen across generations and can produce intra- as well as intergenerational assets and risks. This knowledge about the individual's responsiveness to context and experience has both positive and negative implications across early childhood, adolescence and into adulthood. Sensitive periods for brain growth and development are considered within the contextual factors that influence development including; parental responsiveness and attunement, intentional skill development, mindfulness, reciprocal interactions, adversity, trauma, and enriching opportunities. The accumulated knowledge on human development and the power of context and culture can inform child-serving systems that support positive adaptations, resilience, learning, health, and well-being.