84 Recent breakthroughs in precision medicine have unveiled promising HER2-targeted therapies for extrahepatic cholangiocarcinoma (eCCA) and gallbladder cancer (GBC), according to a comprehensive review published in the European Journal of Cancer. These advancements signal a potential shift in the treatment landscape for these rare and aggressive cancers, traditionally known for their poor prognosis and limited therapeutic options. Biliary tract cancers (BTCs), including eCCA and GBC, are a diverse group of malignancies characterised by late diagnosis and low survival rates. The human epidermal growth factor receptor 2 (HER2), a well-established biomarker in breast and gastric cancers, has emerged as a potential target for BTCs due to the significant alterations observed in these tumours. The current first-line palliative treatments for advanced BTC typically involve a combination of gemcitabine, cisplatin, and immunotherapy. However, despite these efforts, long-term survival remains dismal. Precision medicine, leveraging the HER2 pathway, aims to improve outcomes by offering targeted therapies tailored to the genetic profiles of these cancers. Various anti-HER2 therapies, such as trastuzumab, pertuzumab, trastuzumab-deruxtecan, zanidatamab, and neratinib, have shown potential in clinical trials. These therapies focus on inhibiting the HER2 receptor, thereby disrupting cancer cell growth signals and inducing tumour cell death. The studies that were looked at showed that these targeted treatments worked, especially in eCCA and GBC, which have higher levels of HER2 overexpression and amplification. One important study in the review showed that moderate to strong HER2 expression was found in 19.9% of eCCA cases, which is a lot more than the 1.1% of cases of intrahepatic cholangiocarcinoma (iCCA). Several clinical trials have explored the effectiveness of these targeted therapies. For instance, the SUMMIT trial investigated neratinib, a tyrosine kinase inhibitor, in patients with HER2-mutant advanced BTC. The trial reported an objective response rate (ORR) of 16%, with median progression-free survival (PFS) of 2.8 months and median overall survival (OS) of 5.4 months. Other trials have assessed combinations of HER2 inhibitors with chemotherapy. The MyPathway study looked at what happened when pertuzumab and trastuzumab were used together. It showed promise in treating HER2-positive metastatic BTC. Also, zanidatamab, a new bispecific antibody, is being tested as a first-line treatment for BTC in a phase III trial (HERIZON-BTC-02), along with standard chemotherapy. Despite these encouraging developments, several challenges persist. The relatively small patient populations in these trials and the absence of standardised HER2 assessment protocols for BTC complicate patient selection and treatment evaluation. Furthermore, intrinsic or acquired resistance to HER2-targeted therapies remains a significant hurdle. To overcome these challenges, ongoing clinical trials are focusing on improving the precision of molecular testing and exploring combination therapies that integrate chemotherapy and immunotherapy. The creation of new antibody-drug conjugates (ADCs) and immune-stimulating antibody conjugates (ISACs) could also help HER2-targeted treatments work better. Future research aims to refine these approaches and expand their application beyond advanced disease settings. Using successful methods from treating breast and stomach cancers, HER2-targeted therapies could be used as both neoadjuvant and adjuvant treatments for BTC, which would mean better outcomes for patients.