Dendritic cells (DC) are known to be essential immune cells in innate immunity and in the initiation of adaptive immunity. The shaping of adaptive immunity by innate immunity is dependent on DC unique cellular functions and DC-derived effector molecules such as cytokines and chemokines. Thus, it is not surprising that numerous studies have identified alterations in DC number, function, and subset ratios in various diseases, such as infections, cancers, and autoimmune diseases. Recent evidence has also identified that immunosuppression occurring after severe systemic inflammation, such as found in sepsis, is a result of depletion in DC numbers and a later dysfunction in DC activity. This correlation suggests that the sustained DC dysfunction initiated by life-threatening inflammation may contribute to the subsequent immunoparalysis, potentially as a result of the long-term maintenance of an abnormal gene expression pattern. In this review, we summarized the present information regarding altered DC function after a severe, acute inflammatory response and propose a mechanism, whereby epigenetic changes can influence long-term gene expression patterns by DC, thus supporting an immunosuppression phenotype.