Poly(ADP-Ribose) Polymerase-1 (PARP-1) is the prototypical and most abundantly expressed member of a family of PARPs that catalyze the polymerization of ADP-ribose (ADPR) units from donor NAD+ molecules on target proteins. PARP-1 plays roles in a variety of genomic processes, including the regulation of chromatin structure and transcription in response to specific cellular signals. PARP-1 also plays important roles in many stress-induced disease states. In this chapter, we review the molecular and cellular aspects of PARP-1’s chromatin-modulating activities, as well as the impact that these chromatin-modulating activities have on the regulation of gene expression. In addition, we highlight the potential therapeutic use of drugs that target PARP-1’s enzymatic activity for the treatment of human diseases.