Cells are exposed to diverse stresses; poly(ADP-ribose) polymerase-1 (PARP-1), which processes diverse signals and directs cells to specific fates (survival or death), is a key player in responses to cellular stress. PARP-1 usually uses NAD+ as a donor of ADP-ribose units to regulate the synthesis of poly(ADP-ribose). Over 100 novel substrates of PARP-1 have been identified, most of which are involved in cellular processes such as ribosome biogenesis and transcription regulation. In addition, PARP-1 functions in inflammation by modulating inflammatory-relevant gene expression. PARP-1 also is involved in the tissue damage caused by ischemia/reperfusion conditions. Common inflammatory mediators (inducible nitric oxide synthase, interleukin [IL]-1β, and tumor necrosis factor-α) are regulated by PARP-1, which helps amplify nuclear factor-κB-mediated inflammation. PARP-1 plays a role in adaptive immunity by modulating the ability of dendritic cells to stimulate T cells. The expression of several genes (such as IL-2 and IL-10) and T-cell proliferation also are controlled by the activation of PARP-1. Inhibition of PARP-1 enzymatic activity attenuates the secretion of proinflammatory cytokines and therefore alleviates autoimmune diseases. PARP inhibitors may represent a new avenue for disease treatment.