Poly-(ADP)-ribose polymerases (PARPs) are a family 17 enzymes in humans that have diverse roles in cell biology including innate immune response, DNA repair, and regulation of signaling pathways. PARPs catalyze the transfer of ADP-ribose from nicotinamide adenine dinucleotide (NAD+) to target proteins or biomolecules. This enigmatic post- translational modification comes in two varieties: the transfer of a single unit of ADP-ribose, known as mono-ADP-ribosylation (MARylation) or the transfer of multiple units of ADP-ribose, known as poly-ADP-ribosylation (PARylation). The overarching goal of this work was to leverage chemical tools to further the field’s understanding of the biological roles and regulation of PARPs. The work can be divided into two distinct parts: 1) the development of tools for studying cellular mechanisms and 2) the application of small-molecule tools to uncover previously unknown relationships between writers and erasers of MARylation.