Macrodomains　are　evolutionarily　conserved　structural　elements.　Many　macrodomains　feature　as　binding　modules　of　ADP-ribose,　thus　participating　in　the　recognition　and　removal　of　mono-and　poly-ADP-ribosylation.　Macro　domains　are　involved　in　the　regulation　of　a　variety　of　physiological　processes　and　represent　valuable　therapeutic　targets.　Moreover,　as　part　of　the　nonstructural　proteins　of　certain　viruses,　macrodomains　are　also　pivotal　for　viral　replication　and　pathogenesis.　Thus,　targeting　viral　macro　domains　with　inhibitors　is　considered　to　be　a　promising　antiviral　intervention.　In　this　review,　we　summarize　our　current　understanding　of　human　and　viral　macrodomains　that　are　related　to　mono-ADP-ribosylation,　with　emphasis　on　the　search　for　inhibitors.　The　advances　summarized　here　will　be　helpful　for　the　design　of　macrodomainspecific　agents　for　therapeutic　and　diagnostic　applications.