PGE(2), an essential homeostatic factor, is also a key mediator of immunopathology in chronic infections and cancer. The impact of PGE(2) reflects the balance between its cyclooxygenase 2-regulated synthesis and 15-hydroxyprostaglandin dehydrogenase-driven degradation and the pattern of expression of PGE(2) receptors. PGE(2) enhances its own production but suppresses acute inflammatory mediators, resulting in its predominance at late/chronic stages of immunity. PGE(2) supports activation of dendritic cells but suppresses their ability to attract naive, memory, and effector T cells. PGE(2) selectively suppresses effector functions of macrophages and neutrophils and the Th1-, CTL-, and NK cell-mediated type 1 immunity, but it promotes Th2, Th17, and regulatory T cell responses. PGE(2) modulates chemokine production, inhibiting the attraction of proinflammatory cells while enhancing local accumulation of regulatory T cells cells and myeloid-derived suppressor cells. Targeting the production, degradation, and responsiveness to PGE(2) provides tools to modulate the patterns of immunity in a wide range of diseases, from autoimmunity to cancer.