Abstract Smart microscopy represents a paradigm shift in biological imaging, moving from passive observation tools to active collaborators in scientific inquiry. Enabled by advances in automation, computational power, and artificial intelligence, these systems are now capable of adaptive decision‐making and real‐time experimental control. Here, we introduce a theoretical framework that reconceptualises smart microscopy as a partner in scientific investigation. Central to our framework is the concept of the ‘epistemic–empirical divide’ in cellular investigation, describing the gap between what is observable (empirical domain) and what must be understood (epistemic domain). We propose six core design principles: epistemic–empirical awareness, hierarchical context integration, an evolution from detection to perception, adaptive measurement frameworks, narrative synthesis capabilities, and cross‐contextual reasoning. Together, these principles guide a multi‐agent architecture designed to align empirical observation with the goals of scientific understanding. Our framework provides a roadmap for building microscopy systems that go beyond automation to actively support hypothesis generation, insight discovery, and theory development, redefining the role of scientific instruments in the process of knowledge creation.
Kesavan et al. (2026) studied this question.