<p>Claudin 18.2 (CLDN18.2) has rapidly evolved from a biologically attractive target to a clinically actionable biomarker in HER2-negative advanced gastric and gastroesophageal junction adenocarcinoma. Following the phase 3 SPOTLIGHT and GLOW trials, zolbetuximab plus fluoropyrimidine/platinum chemotherapy has become a valid first-line option for CLDN18.2-positive disease. However, first-line decision-making is now increasingly complex because treatment selection depends on the integration of HER2, CLDN18, PD-L1 combined positive score (CPS), and MSI/MMR, while no direct comparative trial has established the preferred sequence between zolbetuximab-based therapy and immune checkpoint inhibitor (ICI)-based therapy. In this review, we summarize the biological rationale and pivotal clinical evidence supporting CLDN18.2 targeting and focus on the issues most relevant to practice: the differing clinical roles of CLDN18 and PD-L1 CPS as biomarkers, treatment selection in biomarker-overlap cases, the possibility of deferring PD-1 blockade to later lines in selected patients, pathology and testing pitfalls, and the practical implementation of zolbetuximab-based therapy. We further discuss emerging triplet strategies and next-generation CLDN18.2-targeted platforms. Rather than considering CLDN18.2 as an isolated biomarker, we propose a treatment-oriented framework for integrating zolbetuximab into contemporary first-line management of HER2-negative advanced gastric cancer.</p>