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The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. Thus, it is an opportune time to conceive a common framework for microbiome-mediated regulation of immune function. We propose the term conditioned immunity to describe the multifaceted mechanisms by which the microbiome modulates immunity. In this regard, microbial colonization is a conditioning exposure that has durable effects on immune function through the action of secondary metabolites, foreign molecular patterns, and antigens. Here, we discuss how spatial niches impact host exposure to microbial products at the level of dose and timing, which elicit diverse conditioned responses.