Abstract: Diffuse gastric cancer (DGC) is a subtype of gastric adenocarcinoma with low differentiation, high malignancy, and a poor clinical prognosis. DGC is highly heterogeneous and can be driven by mutations in the CDH1, RHOA, and CLDN18-ARHGAP gene fusion and wide-ranging environmental gene mutation interactions. However, its pathogenesis is unclear. The existing DGC models include transgenic mice, patient-derived tumor xenograft (PDX), and organoid models. The organic integration of these models will aid in a more accurate investigation of the pathophysiological process and the mechanism of DCG. In clinical practice, there is a lack of effective drugs for DGC treatment. Although a few molecular-targeted drugs, such as MET and ROS1 inhibitors, have been developed recently, they have not demonstrated any significant clinical efficacy. Thus, in this paper, we look forward to emerging fields such as metagenomics, proteomics, and metabolomics, and explore cutting-edge perspectives such as spatiotemporal heterogeneity of DGC, gastric cancer microecological regulation, and molecular typing for multi-omics integration, to put forward the focus and direction of DGC precision therapy in future, which can provide theoretical reference for DGC precision diagnosis and treatment.