Targeted protein degradation (TPD) is an emerging drug discovery modality that offers the potential to probe biological pathways and target proteins that have previously been considered “undruggable”. Compared to traditional drug discovery approaches where small molecules bind and inhibit the function of a protein of interest (POI), TPD exploits the cell’s own degradation machinery to selectively target a protein for degradation. This offers the potential for improved therapeutic efficacy and the possibility to discover and validate novel targets. In our comprehensive review, we delve into the fundamental principles and unparalleled advantages of TPD. Furthermore, we explore the challenges faced by the field in bringing this transformative modality into the clinic.