Macrophages function as sentinel, cell-regulatory 'hubs' capable of initiating, perpetuating and contributing to the resolution of an inflammatory response, following their activation from a resting state. Highly complex and varied gene expression programs within the macrophage enable such functional diversity. To investigate how programs of gene expression relate to the phenotypic attributes of the macrophage, the development of in silico modeling methods is needed. Such models need to cover multiple scales, from molecular pathways in cell-autonomous immunity and intercellular communication pathways in tissue inflammation to whole organism response pathways in systemic disease. Here, we highlight the potential of in silico macrophage modeling as an amenable and important yet under-exploited tool in aiding in our understanding of the immune inflammatory response. We also discuss how in silico macrophage modeling can help in future therapeutic strategies for modulating both the acute protective effects of inflammation (such as host defense and tissue repair) and the harmful chronic effects (such as autoimmune diseases).