Small-molecule drug discovery has conventionally revolved around the rational design of candidates for binding to functional hydrophobic pockets on a target surface. However, many targets implicated in complex disease states such as cancer lack these binding sites, rendering them “undruggable” and elusive to therapeutic intervention. It is estimated that 85% of disease targets fall into this category, leading to a critical unmet need for the development of new drug modalities to broaden the scope of treatable human disease. Targeted protein degradation (TPD) has emerged as a disruptive therapeutic paradigm with great potential to expand the druggable target space by exploiting the cellular degradation machinery, the ubiquitin-proteasome system (UPS), to induce the degradation of a target protein. Degraders induce a noncanonical interaction between a covalently recruited E3 ligase and a protein of interest, leading to the proximity-induced ubiquitination and subsequent degradation of the target. Of the over 680 known E3 ubiquitin ligases, only a dozen or so to date have been employed for this approach. There is a clear need to identify additional E3 ligases that can be harnessed for TPD, to accommodate a broad range of therapeutically relevant targets with differential localization and expression. This work delineates several efforts to discover chemically ligandable E3 ligases to support targeted protein degradation. Chapter 1 provides a terse overview of ubiquitin biology, the TPD field, and advanced proteomic techniques critical to the work herein. Chapter 2 details the development, validation, and implementation of a pooled CRISPR transcriptional activation screen covering all known E3 ubiquitin ligases to identify FBXO22 as an E3 ligase supporting 4 targeted protein degradation. FBXO22 is broadly overexpressed across cancers and can be recruited to induce the degradation of various intracellular protein targets. Chapter 3 describes the phenotypic screening-based discovery of a recruiter for the FBXW7 R465C mutant E3 ligase, expressed in many stomach and colorectal cancers. The identified recruiter is selective for the R465C mutant over wild-type FBXW7, opening new possibilities for cancer-specific degrader therapies. Overall, targeted protein degradation holds great promise in broadening the scope of treatable human disease, and the work herein substantially contributes to the repertoire of effectors suitable for this purpose.