Although transcription factors are thought to be undruggable owing to lack of active sites, several inhibitors for transcription factor STAT3 have been developed by targeting its SH2 domain to disrupt its dimerization. However, it remains challenging to develop selective STAT3 inhibitors for therapeutic purpose because of the high homology of SH2 domains among STAT family members and the residual activity of STAT3 monomers. Bai et al. utilized proteolysis-targeting chimera (PROTAC) technology to achieve a highly selective STAT3 degrader designated as SD-36 using an optimized STAT3 inhibitor with moderate selectivity linked to the cereblon ligand lenalidomide. SD-36 reduced the protein levels of total and active STAT3 in a time- and dose-dependent manner, while RNA-seq and proteomics analysis showed that SD-36 exhibited high selectivity toward STAT3. Furthermore, SD-36 is >1,000 times more potent than its corresponding STAT3 inhibitor SI-109 in inhibiting the transcriptional activity of STAT3. SD-36 induced growth inhibition in a subset of cancer cell lines with activated STAT3 and achieved complete tumor regression in several xenograft models in mice. This study underlines the advantage of PROTAC technology in pharmaceutical development and provides a successful example of targeting transcription factors.