Signal integration is central to a causal understanding of appropriately scaled inflammatory responses. Here, we discuss recent progress in our understanding of the stimulus-response linkages downstream of pro-inflammatory inputs, with special attention to (1) the impact of cell state on the specificity of evoked gene expression and (2) the critical role of the spatial context of stimulus exposure. Advances in these directions are emerging from new tools for inferring cell-cell interactions and the activities of cytokines and transcription factors in complex microenvironments, enabling analysis of signal integration in tissue settings. Building on data-driven elucidation of factors driving inflammatory outcomes, mechanistic modeling can then contribute to a quantitative understanding of regulatory events that balance protective versus pathological inflammation.