Targeted protein degradation (TPD) is emerging as a promising strategy for chemical knockdown and drug discovery. TPD strategies eliminate disease-associated proteins by hijacking the intracellular proteolysis machinery, including the ubiquitin-proteasome system or the lysosomal pathway. Compared to traditional small-molecular inhibitors, TPD strategies exhibited significant advantages in reducing toxic side effects and the risk of drug resistance, and expanding the target space to “undruggable” proteins. Inspired by our research findings in the field of TPD, this review aims to summarize recent advances of major TPD technologies, e.g., proteolysis targeting chimaera, molecular glue, lysosome-targeting chimaera, autophagosome-tethering compound, autophagy-targeting chimera, and discuss their potential applications and developing trend.