Poly (ADP-robose) glycohydrolase (PARG) is a catabolic enzyme that cleaves ADP-ribose polymers synthesized by members of the poly (ADP-ribose) polymerase (PARP) family of enzymes. The growing evidence supports the importance of a tight control of poly (ADP-ribose) metabolism by the two major enzymes, PARP-1 and PARG. Recent studies have advanced the understanding of PARPs' and PARG's functions in various cellular and physiological processes. In the last 10 years, homeostasis of poly (ADP-ribosyl)ation has been a target of pharmaceutical interventions for various pathologies. Although the polymer synthesizing enzyme PARP-1 has been well studied, the function of PARG remains largely unknown. However, a great effort has been made in recent years to delineate biological functions of PARG and to explore the therapeutical potentials of PARG inhibition in pathophysiological conditions such as inflammation, ischemia, stroke, and cancer chemotherapy.