Purpose of Review <p>Human epidermal growth factor receptor 2 (HER2) is a critical target in advanced gastric cancer (AGC). This review highlights the current treatment landscape, lessons learned from past clinical trials, and prospects for future treatment strategies for HER2-positive AGC.</p> Recent Findings <p>Trastuzumab had been the standard treatment for HER2-positive AGC for a decade, and subsequently, trastuzumab deruxtecan, an antibody–drug conjugate (ADC), emerged with an impressive response. Recently, the addition of pembrolizumab to first-line chemotherapy plus trastuzumab has become a novel standard treatment. Past clinical trials of HER2-targeted therapies, which succeeded in HER2-positive breast cancer but failed in AGC, have deepened our understanding of resistance mechanisms. Based on these results, several clinical trials of novel HER2-targeted therapies, including immunologic approaches such as CAR-T cells and vaccines, are currently ongoing. Circulating tumor DNA is also expected to be a tool for real-time biomarker analysis. Additionally, ADCs with a bystander effect have the potential to expand the scope of HER2-targeted therapies to HER2-expressing, including HER2-low AGC.</p> Summary <p>Learning from past trials, further development of novel HER2-targeted therapies is underway, expanding their scope to HER2-expressing AGC. Meanwhile, selecting optimal treatment is a challenging issue in cases with HER2-low AGC overlapping with other biomarkers like CLDN18.2.</p>