The macro module is a globular protein domain of about 25 kDa that is evolutionarily conserved in organisms from viruses, bacteria, yeast to humans. It is generally part of proteins that have wide-ranging (and yet to be discovered) cellular functions. There are several examples of macro domains associated with modules showing homology to poly-ADP-ribosyl-polymerases. Many macro domains, including those of the human histone macroH2A1.1, bind NAD metabolites such as ADP-ribose, suggesting that macro domains may function in the recognition of this and related molecules. The presence of a metabolite-binding function in a repressive chromatin component opens new potential connections between chromosome structure, gene silencing and cellular metabolism. Current evidence suggests that macro domains also represent a novel tool for studying NAD metabolites and may be an attractive drug target for the treatment of diseases.