The milestone of Adenosine Diphosphate-ribosylation studies was the paper by Paul Mandel’s group in 1960s, first describing a “sort” of polyadenylic acid synthesized upon addition of nicotinamide mononucleotide in rat liver nuclear extracts. Nicotinic Acid or Niacin is the precursor of Nicotinamide Adenin Dinucleotide. In 1960s this compound was known mainly as coenzyme of most redox processes in metabolism. The discovery of enzymes that covalently transfer Adenosine Diphosphate-ribose moiety of Nicotinamide Adenin Dinucleotide to acceptor proteins, thereby altering their function, or are able to synthesize cyclic Adenosine Diphosphate-ribose, has given rise to the era of one of the most studied and still surprising reversible post – translational modification reactions. Over 50 years, developing the research on Adenosine Diphosphate-ribosylation has provided the basis to interconnect several processes thought to be very distant each other, opening new perspectives in their regulation and in therapeutic intervention. Here a synthesis of the history and the main and recent goals reached studying Adenosine Diphosphate-ribose in all its features are provided by a series of reviews including the most advanced research.