Abstract: Proteolysis-targeting chimeras (PROTACs) are small-molecule protein degraders based on the ubiquitin-proteasome system. Recently, the development of specific small-molecule ligands for several E3 ligases (CRL4^CRBN, CRL2^VHL and cIAP) have significantly advanced the PROTACs technology. Several PROTACs against various oncogenic proteins including bromodomain-containing protein 4 (BRD4), estrogen receptor (ER) and androgen receptor (AR) have been developed and considered a novel approach for therapy of cancers. There are advantages of the new technology over the traditional small-molecule strategies. This review article provides a summary on the recent progress in the small-molecule-based PROTACs as antitumor drugs, and the challenges of this technology.