Cancer cells respond to increases in DNA damage by upregulating their DNA damage response (DDR). The base excision repair (BER) pathway corrects damage to single DNA bases through the action of multiple enzymes, including the central protagonist, apurinic/apyrimidinic endonuclease 1 (APE1). Numerous studies have shown association between increased APE1 levels and enhanced growth, migration, and drug resistance in human tumor cells, as well as with decreased patient survival. APE1 has been implicated in over 20 human cancers, making this an attractive target for developing anticancer therapies. Despite intensive effort, there are currently no clinical endonuclease inhibitors of APE1. We have used a newly developed high-throughput protein X-ray crystallography-based fragment screen to obtain starting points for the design of molecules to block APE1 function. Starting with a proprietary fragment library, we obtained high quality fragment-bound crystal structures showing diversity of chemical matter and hit location, representing the first experimental 3D structures of APE1 bound to drug-like molecules, thereby resolving a primary bottleneck in the path to inhibitor development. The implementation of this unique lead discovery campaign has facilitated three independent strategies toward the development of APE1 inhibitors, including (i) fragment growing and elaboration of hits bound at the endonuclease site; (ii) linking of fragments bound to distinct but proximally located sites, and (iii) use of fragments for the design of hooks to use in targeted protein degradation (TPD) strategies. We are using a combination of computational and medicinal chemistry, structural biology, and biochemical and biophysical studies and will discuss our progress towards these goals.