Cancer remains a significant global health concern, which entails the development of innovative and targeted therapies with reduced adverse effects and drug resistance. In recent years, the concept of Proteolysis-Targeting Chimeras (PROTACs) has emerged as a promising strategy in drug discovery for cancer treatment. PROTACs exploit the cell’s own protein degradation system to selectively eliminate disease-causing proteins, offering advantages over traditional small-molecule inhibitors. This chapter provides a comprehensive overview of PROTACs, discussing their principles, recent advancements, and potential in anticancer drug discovery. The principles of PROTACs involve the design of bifunctional molecules that recruit both a target protein and an E3 ubiquitin ligase, leading to the degradation of the target protein via the ubiquitin-proteasome system. Recent progress in PROTAC design has focused on optimizing linker length, warhead selection, and E3 ligase engagement to enhance potency and selectivity. PROTACs have demonstrated promising results in preclinical studies for various cancers, including prostate, breast, and lung cancers. Moreover, advancements in clinical translation have led to the development of several lead PROTACs currently used in clinical trials for prostate cancer, breast cancer, and other malignancies. Despite these advancements, challenges such as specificity, delivery, resistance mechanisms, and off-target effects remain to be addressed. Future research directions include improving specificity with innovative delivery systems, exploring combination therapies to overcome resistance, and advancing PROTACs from preclinical studies to clinical trials. Overall, PROTACs hold immense potential as a targeted therapy for cancer treatment, representing one of the most exciting areas of drug discovery today.