In this commentary, we have suggested that the fibroblast should be considered a sentinel cell. This concept is based on the fibroblast's ability to function both as a structural element and as a vital immunoregulatory cell. In some tissues, these capabilities may be ascribable to subsets of fibroblasts, rather than to some of the general fibroblast populations. The pioneering research of Xia et al, as well as that of others, highlights the need to explore the importance of fibroblasts as playing critical roles in disease. Emerging concepts regarding tissue-specific fibroblasts and fibroblast heterogeneity need to be considered in studies of their biosynthetic capabilities. Of special importance is the recent insight that the NF kappa B/RelB family of transcription proteins have apparently different regulatory roles in fibroblasts and hematopoietic cells. Therefore, with regard to therapeutic strategies targeting molecules such as RelB, caution should be exercised as their interruption may have very different consequences in macrophages compared with fibroblasts. For example, inhibition of RelB in macrophages may well prevent enhanced chemokine expression, whereas in fibroblasts, a critical governor for preventing chemokine expression would be lost. Overall, this could lead to exacerbation of inflammation rather than to an attenuation of the process.