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As biological science rapidly generates new knowledge and novel approaches to address increasingly complex and integrative questions, biology educators face the challenge of teaching the next generation of biologists and citizens the skills and knowledge to enable them to keep pace with a dynamic field. Fundamentally, biology is the science of living systems. Not surprisingly, systems is a theme that pervades national reports on biology education reform. In this essay, we present systems as a unifying paradigm that provides a conceptual framework for all of biology and a way of thinking that connects and integrates concepts with practices. To translate the systems paradigm into concrete outcomes to support instruction and assessment in the classroom, we introduce the biology systems-thinking (BST) framework, which describes four levels of systems-thinking skills: 1) describing a system’s structure and organization, 2) reasoning about relationships within the system, 3) reasoning about the system as a whole, and 4) analyzing how a system interacts with other systems. We conclude with a series of questions aimed at furthering conversations among biologists, biology education researchers, and biology instructors in the hopes of building support for the systems paradigm.