A growing body of literature and clinical evidence shows that newly evolving therapeutic modalities resulting in targeted protein degradation hold promise where catalytic, event-driven mechanisms of target modulation are intractable or exquisite selectivity is challenging, thereby offering new therapeutic potential to drug the “undruggable.” PROTACS (PROteolysis-TArgeting Chimeras) are hetero-bifunctional molecules comprising a ligand that binds the target protein, a chemical linker and a E3 ligase recognition moiety. The resulting PROTAC molecule then specifically recruits the E3 ligase ubiquitin machinery to the target protein of interest (POI) and exploits the cellular ubiquitin proteasome system (UPS) or lysosomal degradation pathways to degrade the protein. PROTAC design to subsequent degradation of the POI is a multifaceted process, requiring cellular assays that interrogate and provide both structure–activity relationship (SAR) data at high-throughput scale and mechanistic data to elucidate target binding, ternary complex formation, ubiquitination and ultimately degradation. In this chapter we will discuss how this approach to PROTAC discovery and optimization has been developed within AstraZeneca and focus on the plate-based cellular assays utilized to enable this evolving modality.