My research program combines chemistry and molecular design to develop novel chemical tools to answer biological questions. Our overall interests are in two main areas: 1. uncovering new roles for nicotinamide adenine dinucleotide (NAD+) regulation in cells and 2. elucidating the function of post-translational modifications (PTMs) by enzymes that use NAD+ as a substrate. A current focus in on the evolutionarily conserved PTM known as ADP-ribosylation. We seek to understanding the impact ADP-ribosylation on cell function as a strategy for therapeutic development. ADP-ribosylation is catalyzed by a family of enzymes known as poly-ADP-ribose polymerases (PARPs, 17 in humans; also referred to as ARTDs), and involves the transfer of ADP-ribose from NAD+ to amino acids in target proteins. Despite being called PARPs, most (12, referred to as mono-PARPs) of the family members catalyze mono-ADP-ribosylation (MARylation) and not poly-ADP-ribosylation (PARylation). Over the last several years we have developed novel chemical tools and approaches, including orthogonal NAD+ analogue-enzyme pairs, selective PARP inhibitors, an NAD+ biosensor, which have provided insights into NAD+ regulation and the function of PARP-mediated MARylation in ways not attainable with conventional methods.