Targeted protein degradation mediated by small molecule degraders represents an exciting new therapeutic opportunity to eliminate disease-causing proteins. These molecules recruit E3 ubiquitin ligases to the protein of interest and mediate its ubiquitination and subsequent proteolysis by the proteasome. Significant advancements have been made in the discovery and development of clinically relevant degraders. In this review we will focus on the recent progress in understanding ternary complex formation and structures, ubiquitination, and other critical factors that govern the efficiency of degraders both in vitro and in vivo. With deeper knowledges of these areas, the field is building guiding principles to reduce the level of empiricism and to identify therapeutically relevant degraders more rationally and efficiently.