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Meaning-making is the process by which a system responds to an indeterminate signal. This article focuses on meaning-making in living systems. It proposes several guidelines for studying the process of meaning-making in living systems in general, and in the immune system in particular. Drawing on a general framework for studying meaning-making in living systems, I suggest three basic organizing concepts for studying meaning-making—variability of the signal, context markers, and transgradience. Those concepts present a radical alternative to the information-processing approach that governs biological research and may shed new light on biological processes.